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1.
  • Clark, Andrew G., et al. (författare)
  • Evolution of genes and genomes on the Drosophila phylogeny
  • 2007
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
  • Tidskriftsartikel (refereegranskat)abstract
    • Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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2.
  • Ademuyiwa, Adesoji O., et al. (författare)
  • Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
  • 2016
  • Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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3.
  • Pircs, Karolina, et al. (författare)
  • Distinct subcellular autophagy impairments in induced neurons from patients with Huntington's disease
  • 2022
  • Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 145:9, s. 3035-3057
  • Tidskriftsartikel (refereegranskat)abstract
    • Huntington's disease (HD) is a neurodegenerative disorder caused by CAG expansions in the huntingtin (HTT) gene. Modelling Huntington's disease is challenging, as rodent and cellular models poorly recapitulate the disease as seen in aging humans. To address this, we generated induced neurons (iNs) through direct reprogramming of human skin fibroblasts, which retain age-dependent epigenetic characteristics. HD-iNs displayed profound deficits in autophagy, characterised by reduced transport of late autophagic structures from the neurites to the soma. These neurite-specific alterations in autophagy resulted in shorter, thinner and fewer neurites specifically in HD-iNs. CRISPRi-mediated silencing of HTT did not rescue this phenotype but rather resulted in additional autophagy alterations in ctrl-iNs, highlighting the importance of wild type HTT in normal neuronal autophagy. In summary, our work identifies a distinct subcellular autophagy impairment in adult patient derived Huntington's disease neurons and provides a new rational for future development of autophagy activation therapies.
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4.
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5.
  • Swallow, Diane M A, et al. (författare)
  • Statins are underused in recent-onset Parkinson's disease with increased vascular risk : findings from the UK Tracking Parkinson's and Oxford Parkinson's Disease Centre (OPDC) discovery cohorts
  • 2016
  • Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 87:11, s. 1183-1190
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Cardiovascular disease (CVD) influences phenotypic variation in Parkinson's disease (PD), and is usually an indication for statin therapy. It is less clear whether cardiovascular risk factors influence PD phenotype, and if statins are prescribed appropriately.OBJECTIVES: To quantify vascular risk and statin use in recent-onset PD, and examine the relationship between vascular risk, PD severity and phenotype.METHODS: Cardiovascular risk was quantified using the QRISK2 calculator (high ≥20%, medium ≥10 and <20%, low risk <10%). Motor severity and phenotype were assessed using the Movement Disorder Society Unified PD Rating Scale (UPDRS) and cognition by the Montreal cognitive assessment.RESULTS: In 2909 individuals with recent-onset PD, the mean age was 67.5 years (SD 9.3), 63.5% were men and the mean disease duration was 1.3 years (SD 0.9). 33.8% of cases had high vascular risk, 28.7% medium risk, and 22.3% low risk, while 15.2% of cases had established CVD. Increasing vascular risk and CVD were associated with older age (p<0.001), worse motor score (p<0.001), more cognitive impairment (p<0.001) and worse motor phenotype (p=0.021). Statins were prescribed in 37.2% with high vascular risk, 15.1% with medium vascular risk and 6.5% with low vascular risk, which compared with statin usage in 75.3% of those with CVD.CONCLUSIONS: Over 60% of recent-onset PD patients have high or medium cardiovascular risk (meriting statin usage), which is associated with a worse motor and cognitive phenotype. Statins are underused in these patients, compared with those with vascular disease, which is a missed opportunity for preventive treatment.TRIAL REGISTRATION NUMBER: GN11NE062, NCT02881099.
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6.
  • Garza, Raquel, et al. (författare)
  • LINE-1 retrotransposons drive human neuronal transcriptome complexity and functional diversification
  • 2023
  • Ingår i: Science Advances. - 2375-2548. ; 9:44
  • Tidskriftsartikel (refereegranskat)abstract
    • The genetic mechanisms underlying the expansion in size and complexity of the human brain remain poorly understood. Long interspersed nuclear element-1 (L1) retrotransposons are a source of divergent genetic information in hominoid genomes, but their importance in physiological functions and their contribution to human brain evolution are largely unknown. Using multiomics profiling, we here demonstrate that L1 promoters are dynamically active in the developing and the adult human brain. L1s generate hundreds of developmentally regulated and cell type-specific transcripts, many that are co-opted as chimeric transcripts or regulatory RNAs. One L1-derived long noncoding RNA, LINC01876, is a human-specific transcript expressed exclusively during brain development. CRISPR interference silencing of LINC01876 results in reduced size of cerebral organoids and premature differentiation of neural progenitors, implicating L1s in human-specific developmental processes. In summary, our results demonstrate that L1-derived transcripts provide a previously undescribed layer of primate- and human-specific transcriptome complexity that contributes to the functional diversification of the human brain.
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7.
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8.
  • Williams-Gray, Caroline H, et al. (författare)
  • Serum immune markers and disease progression in an incident Parkinson's disease cohort (ICICLE-PD)
  • 2016
  • Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 31:7, s. 995-1003
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The immune system is a promising therapeutic target for disease modification in Parkinson's disease (PD), but appropriate immune-related biomarkers must be identified to allow patient stratification for trials and tracking of therapeutic effects. The objective of this study was to investigate whether immune markers in peripheral blood are candidate prognostic biomarkers through determining their relationship with disease progression in PD.METHODS: Serum samples were collected in incident PD cases and age-matched controls. Subjects were clinically evaluated at baseline and 18 and 36 months. Ten cytokines and C-reactive protein were measured, with data reduction using principal-component analysis, and relationships between component scores and motor (MDS Unified Parkinson's Disease Rating Scale - part 3) and cognitive (Mini Mental State Examination [MMSE]) measures of disease severity/progression were investigated.RESULTS: TNF-α, IL1-β, IL-2, and IL-10 were higher in PD (n = 230) than in controls (n = 93), P ≤ 0.001). Principal-component analysis of log-transformed data resulted in a 3-component solution explaining 51% of the variance. Higher "proinflammatory" and lower "anti-inflammatory" component scores were associated with more rapid motor progression over 36 months (P < 0.05), and higher "proinflammatory" component scores were associated with lower MMSE at all times (P < 0.05). Multiple linear regression analysis with adjustment for covariates confirmed "anti-inflammatory" component score was the strongest predictor of slower motor progression (β = -0.22, P = 0.002), whereas proinflammatory cytokines were associated with lower baseline MMSE (β = -0.175, P = 0.007).CONCLUSIONS: Serum immune marker profile is predictive of disease progression in PD and hence a potential prognostic biomarker. However, interventional trials are needed to clarify whether peripheral immune changes causally contribute to the progression of PD. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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9.
  • Barker, Roger A., et al. (författare)
  • GDNF and Parkinson's Disease : Where Next? A Summary from a Recent Workshop
  • 2020
  • Ingår i: Journal of Parkinson's Disease. - 1877-7171. ; 10:3, s. 875-891
  • Tidskriftsartikel (refereegranskat)abstract
    • The concept of repairing the brain with growth factors has been pursued for many years in a variety of neurodegenerative diseases including primarily Parkinson's disease (PD) using glial cell line-derived neurotrophic factor (GDNF). This neurotrophic factor was discovered in 1993 and shown to have selective effects on promoting survival and regeneration of certain populations of neurons including the dopaminergic nigrostriatal pathway. These observations led to a series of clinical trials in PD patients including using infusions or gene delivery of GDNF or the related growth factor, neurturin (NRTN). Initial studies, some of which were open label, suggested that this approach could be of value in PD when the agent was injected into the putamen rather than the cerebral ventricles. In subsequent double-blind, placebo-controlled trials, the most recent reporting in 2019, treatment with GDNF did not achieve its primary end point. As a result, there has been uncertainty as to whether GDNF (and by extrapolation, related GDNF family neurotrophic factors) has merit in the future treatment of PD. To critically appraise the existing work and its future, a special workshop was held to discuss and debate this issue. This paper is a summary of that meeting with recommendations on whether there is a future for this therapeutic approach and also what any future PD trial involving GDNF and other GDNF family neurotrophic factors should consider in its design.
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10.
  • Drouin-Ouellet, Janelle, et al. (författare)
  • REST suppression mediates neural conversion of adult human fibroblasts via microRNA-dependent and -independent pathways
  • 2017
  • Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 9:8, s. 1117-1131
  • Tidskriftsartikel (refereegranskat)abstract
    • Direct conversion of human fibroblasts into mature and functional neurons, termed induced neurons (iNs), was achieved for the first time 6 years ago. This technology offers a promising shortcut for obtaining patient- and disease-specific neurons for disease modeling, drug screening, and other biomedical applications. However, fibroblasts from adult donors do not reprogram as easily as fetal donors, and no current reprogramming approach is sufficiently efficient to allow the use of this technology using patient-derived material for large-scale applications. Here, we investigate the difference in reprogramming requirements between fetal and adult human fibroblasts and identify REST as a major reprogramming barrier in adult fibroblasts. Via functional experiments where we overexpress and knockdown the REST-controlled neuron-specific microRNAs miR-9 and miR-124, we show that the effect of REST inhibition is only partially mediated via microRNA up-regulation. Transcriptional analysis confirmed that REST knockdown activates an overlapping subset of neuronal genes as microRNA overexpression and also a distinct set of neuronal genes that are not activated via microRNA overexpression. Based on this, we developed an optimized one-step method to efficiently reprogram dermal fibroblasts from elderly individuals using a single-vector system and demonstrate that it is possible to obtain iNs of high yield and purity from aged individuals with a range of familial and sporadic neurodegenerative disorders including Parkinson's, Huntington's, as well as Alzheimer's disease.
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11.
  • Gallo, Valentina, et al. (författare)
  • Exploring causality of the association between smoking and Parkinson's disease
  • 2019
  • Ingår i: International Journal of Epidemiology. - : Oxford University Press (OUP). - 1464-3685 .- 0300-5771. ; 48:3, s. 912-925
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The aim of this paper is to investigate the causality of the inverse association between cigarette smoking and Parkinson's disease (PD). The main suggested alternatives include a delaying effect of smoking, reverse causality or an unmeasured confounding related to a low-risk-taking personality trait. METHODS: A total of 715 incident PD cases were ascertained in a cohort of 220 494 individuals from NeuroEPIC4PD, a prospective European population-based cohort study including 13 centres in eight countries. Smoking habits were recorded at recruitment. We analysed smoking status, duration, and intensity and exposure to passive smoking in relation to PD onset. RESULTS: Former smokers had a 20% decreased risk and current smokers a halved risk of developing PD compared with never smokers. Strong dose-response relationships with smoking intensity and duration were found. Hazard ratios (HRs) for smoking <20 years were 0.84 [95% confidence interval (CI) 0.67-1.07], 20-29 years 0.73 (95% CI 0.56-0.96) and >30 years 0.54 (95% CI 0.43-0.36) compared with never smokers. The proportional hazard assumption was verified, showing no change of risk over time, arguing against a delaying effect. Reverse causality was disproved by the consistency of dose-response relationships among former and current smokers. The inverse association between passive smoking and PD, HR 0.70 (95% CI 0.49-0.99) ruled out the effect of unmeasured confounding. CONCLUSIONS: These results are highly suggestive of a true causal link between smoking and PD, although it is not clear which is the chemical compound in cigarette smoking responsible for the biological effect.
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12.
  • Gustavsson, Emil K., et al. (författare)
  • The annotation of GBA1 has been concealed by its protein-coding pseudogene GBAP1
  • 2024
  • Ingår i: Science Advances. - 2375-2548. ; 10:26, s. 1-20
  • Tidskriftsartikel (refereegranskat)abstract
    • Mutations in GBA1 cause Gaucher disease and are the most important genetic risk factor for Parkinson’s disease. However, analysis of transcription at this locus is complicated by its highly homologous pseudogene, GBAP1. We show that >50% of short RNA-sequencing reads mapping to GBA1 also map to GBAP1. Thus, we used long-read RNA sequencing in the human brain, which allowed us to accurately quantify expression from both GBA1 and GBAP1. We discovered significant differences in expression compared to short-read data and identify currently unannotated transcripts of both GBA1 and GBAP1. These included protein-coding transcripts from both genes that were translated in human brain, but without the known lysosomal function—yet accounting for almost a third of transcription. Analyzing brain-specific cell types using long-read and single-nucleus RNA sequencing revealed region-specific variations in transcript expression. Overall, these findings suggest nonlysosomal roles for GBA1 and GBAP1 with implications for our understanding of the role of GBA1 in health and disease.
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13.
  • Haniffa, Muzlifah, et al. (författare)
  • A roadmap for the Human Developmental Cell Atlas
  • 2021
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 597:7875, s. 196-205
  • Tidskriftsartikel (refereegranskat)abstract
    • This Perspective outlines the Human Developmental Cell Atlas initiative, which uses state-of-the-art technologies to map and model human development across gestation, and discusses the early milestones that have been achieved. The Human Developmental Cell Atlas (HDCA) initiative, which is part of the Human Cell Atlas, aims to create a comprehensive reference map of cells during development. This will be critical to understanding normal organogenesis, the effect of mutations, environmental factors and infectious agents on human development, congenital and childhood disorders, and the cellular basis of ageing, cancer and regenerative medicine. Here we outline the HDCA initiative and the challenges of mapping and modelling human development using state-of-the-art technologies to create a reference atlas across gestation. Similar to the Human Genome Project, the HDCA will integrate the output from a growing community of scientists who are mapping human development into a unified atlas. We describe the early milestones that have been achieved and the use of human stem-cell-derived cultures, organoids and animal models to inform the HDCA, especially for prenatal tissues that are hard to acquire. Finally, we provide a roadmap towards a complete atlas of human development.
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14.
  • Li, Weihua, et al. (författare)
  • 11C-PE2I and 18F-Dopa PET for assessing progression rate in Parkinson's : A longitudinal study
  • 2018
  • Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 33:1, s. 117-127
  • Tidskriftsartikel (refereegranskat)abstract
    • 18F-dopa PET measuring aromatic l-amino acid decarboxylase activity is regarded as the gold standard for evaluating dopaminergic function in Parkinson's disease. Radioligands for dopamine transporters are also used in clinical trials and for confirming PD diagnosis. Currently, it is not clear which imaging marker is more reliable for assessing clinical severity and rate of progression. The objective of this study was to directly compare 18F-dopa with the highly selective dopamine transporter radioligand 11C-PE2I for the assessment of motor severity and rate of progression in PD. Thirty-three mild-moderate PD patients underwent 18F-dopa and 11C-PE2I PET at baseline. Twenty-three were followed up for 18.8 ± 3.4 months. Standard multiple regression at baseline indicated that 11C-PE2I BPND predicted UPDRS-III and bradykinesia-rigidity scores (P < 0.05), whereas 18F-dopa Ki did not make significant unique explanatory contributions. Voxel-wise analysis showed negative correlations between 11C-PE2I BPND and motor severity across the whole striatum bilaterally. 18F-Dopa Ki clusters were restricted to the most affected putamen and caudate. Longitudinally, negative correlations were found between striatal (increment)11C-PE2I BPND, (increment)UPDRS-III, and (increment)bradykinesia-rigidity, whereas no significant associations were found for (increment)18F-dopa Ki. One cluster in the most affected putamen was identified in the longitudinal voxel-wise analysis showing a negative relationship between (increment)11C-PE2I BPND and (increment)bradykinesia-rigidity. Striatal 11C-PE2I appears to show greater sensitivity for detecting differences in motor severity than 18F-dopa. Furthermore, dopamine transporter decline is closely associated with motor progression over time, whereas no such relationship was found with aromatic l-amino acid decarboxylase. 11C-PE2I may be more effective for evaluating the efficacy of neuroprotective treatments in PD.
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15.
  • Pircs, Karolina, et al. (författare)
  • Huntingtin Aggregation Impairs Autophagy, Leading to Argonaute-2 Accumulation and Global MicroRNA Dysregulation
  • 2018
  • Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 24:6, s. 1397-1406
  • Tidskriftsartikel (refereegranskat)abstract
    • Many neurodegenerative diseases are characterized by the presence of intracellular protein aggregates, resulting in alterations in autophagy. However, the consequences of impaired autophagy for neuronal function remain poorly understood. In this study, we used cell culture and mouse models of huntingtin protein aggregation as well as post-mortem material from patients with Huntington's disease to demonstrate that Argonaute-2 (AGO2) accumulates in the presence of neuronal protein aggregates and that this is due to impaired autophagy. Accumulation of AGO2, a key factor of the RNA-induced silencing complex that executes microRNA functions, results in global alterations of microRNA levels and activity. Together, these results demonstrate that impaired autophagy found in neurodegenerative diseases not only influences protein aggregation but also directly contributes to global alterations of intracellular post-transcriptional networks. Pircs et al. report that aggregation of the mutant huntingtin protein, a hallmark of Huntington's disease proteinopathy, impairs macroautophagy, leading to Argonaute-2 accumulation and global dysregulation of microRNAs. These results indicate that autophagy not only influences protein aggregation but also directly contributes to the global alterations of post-transcriptional networks in Huntington's disease.
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16.
  • Wood, Nigel I., et al. (författare)
  • Increased thirst and drinking in Huntington's disease and the R6/2 mouse
  • 2008
  • Ingår i: Brain Research Bulletin. - : Elsevier BV. - 0361-9230. ; 76:1-2, s. 70-79
  • Tidskriftsartikel (refereegranskat)abstract
    • While Huntington's disease (HD) is a condition that primarily involves the basal ganglia, there is evidence to suggest that the hypothalamus is also affected. Because the osmoreceptors regulating thirst are situated in the circumventricular region of the hypothalamus, we were interested in whether altered thirst is a part of the HD phenotype. We used the LABORAS behavioural monitoring system and water consumption to show that drinking behaviour was abnormal in R6/2 mice. By 10 weeks of age, R6/2 mice spent significantly more time drinking and drank a greater volume than their wild-type (WT) littermates. The numbers of immunoreactive vasopressin neurons in the paraventricular nucleus (PVN) of the hypothalamus in R6/2 mice were significantly decreased from 8 weeks of age, suggesting that the change in drinking behaviour may be the result of hypothalamic dysfunction. We gave a xerostomia (dry mouth) questionnaire to HD patients and control subjects, and also measured their urine osmolality and serum vasopressin. The mean total xerostomia score was significantly higher in HD patients than in controls, indicating greater thirst in HD patients. Urine osmolality was unaffected in HD patients up to clinical stage 111, and none of the patients had diabetes. However, serum vasopressin was increased, suggesting a dysregulation in the control of hypothalamic vasopressin release. A dry mouth can affect taste, mastication and swallowing, all of which may contribute to the significant weight loss seen in both HD patients and R6/2 mice, as can dehydration. We suggest that increased thirst may be an important and clinically relevant biomarker for the study of disease progression in HD.
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17.
  • Barker, Roger A., et al. (författare)
  • A new approach to disease-modifying drug trials in Parkinson's disease
  • 2013
  • Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 123:6, s. 2364-2365
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Translating new findings in the laboratory into therapies for patients is a slow and expensive process. The development of therapies for neurodegenerative diseases is further complicated by the difficulty in determining whether the drug truly retards the slow degenerative process or provides only symptomatic benefit. In this issue, Aviles-Olmos et al. describe a first in Parkinson's disease (PD) patient study using a drug previously approved for diabetes treatment. In addition to suggesting that the drug may indeed be disease modifying in PD, their innovative approach suggests there may be more rapid and inexpensive avenues for testing novel therapies in PD.
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18.
  • Barker, Roger A, et al. (författare)
  • Animal Models of Parkinson's Disease : Are They Useful or Not?
  • 2020
  • Ingår i: Journal of Parkinson's Disease. - 1877-718X. ; 10:4, s. 1335-1342
  • Forskningsöversikt (refereegranskat)abstract
    • The use of animal models in Parkinson's disease research has been controversial in terms of how well they relate to the clinical condition and thus their utility for translating therapies from the lab to the clinic. In this article, two researchers debate this issue with Roger Barker taking the view that such models are not useful and may even be misleading, while Anders Björklund defends their use and highlights their value in better understanding and treating this condition.
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19.
  • Barker, Roger A, et al. (författare)
  • Are Stem Cell-Based Therapies for Parkinson's Disease Ready for the Clinic in 2016?
  • 2016
  • Ingår i: Journal of Parkinson's Disease. - 1877-718X. ; 6:1, s. 57-63
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent news of an impending clinical cell transplantation trial in Parkinson's disease using parthenogenetic stem cells as a source of donor tissue have raised hopes in the patient community and sparked discussion in the research community. Based on discussions held by a global collaborative initiative on translation of stem cell therapy in Parkinson's disease, we have identified a set of key questions that we believe should be addressed ahead of every clinical stem cell-based transplantation trial in this disorder. In this article, we first provide a short history of cell therapy in Parkinson's disease and briefly describe the current state-of-art regarding human stem cell-derived dopamine neurons for use in any patient trial. With this background information as a foundation, we then discuss each of the key questions in relation to the upcoming therapeutic trial and critically assess if the time is ripe for clinical translation of parthenogenetic stem cell technology in Parkinson's disease.
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20.
  • Barker, Roger A., et al. (författare)
  • Designing stem-cell-based dopamine cell replacement trials for Parkinson’s disease
  • 2019
  • Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 25, s. 1045-1053
  • Tidskriftsartikel (refereegranskat)abstract
    • Clinical studies of Parkinson’s disease (PD) using a dopamine cell replacment strategy have been tried for more than 30 years. The outcomes following transplantation of human fetal ventral mesencephalic tissue (hfVM) have been variable, with some patients coming off their anti-PD treatment for many years and others not responding and/or developing significant side effects, including graft-induced dyskinesia. This led to a re-appraisal of the best way to do such trials, which resulted in a new European-Union-funded allograft trial with fetal dopamine cells across several centers in Europe. This new trial, TRANSEURO (NCT01898390), is an open-label study in which some individuals in a large observational cohort of patients with mild PD who were undergoing identical assessments were randomly selected to receive transplants of hfVM. The TRANSEURO trial is currently ongoing as researchers have completed both recruitment into a large multicenter observational study of younger onset early-stage PD and transplantation of hfVM in 11 patients. While completion of TRANSEURO is not expected until 2021, we feel that sharing the rationale for the design of TRANSEURO, along with the lessons we have learned along the way, can help inform researchers and facilitate planning of transplants of dopamine-producing cells derived from human pluripotent stem cells for future clinical trials.
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21.
  • Barker, Roger A., et al. (författare)
  • Human Trials of Stem Cell-Derived Dopamine Neurons for Parkinson's Disease : Dawn of a New Era
  • 2017
  • Ingår i: Cell Stem Cell. - : Elsevier BV. - 1934-5909. ; 21:5, s. 569-573
  • Tidskriftsartikel (refereegranskat)abstract
    • Stem cell-based therapies for Parkinson's disease are moving into a new and exciting era, with several groups pursuing clinical trials with pluripotent stem cell (PSC)-derived dopamine neurons. As many groups have ongoing or completed GMP-level cell manufacturing, we highlight key clinical translation considerations from our recent fourth GForce-PD meeting. Stem cell-based therapies for Parkinson's disease are moving into a new and exciting era, with several groups pursuing clinical trials with pluripotent stem cell (PSC)-derived dopamine neurons. As many groups have ongoing or completed GMP-level cell manufacturing, we highlight key clinical translation considerations from our recent fourth GForce-PD meeting.
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22.
  • Barker, Roger A, et al. (författare)
  • Immune problems in central nervous system cell therapy
  • 2004
  • Ingår i: NeuroRx. - : Springer Science and Business Media LLC. - 1545-5343. ; 1:4, s. 472-481
  • Tidskriftsartikel (refereegranskat)abstract
    • Transplantation of cells and tissues to the mammalian brain and CNS has revived the interest in the immunological status of brain and its response to grafted tissue. The previously held view that the brain was an absolute "immunologically privileged site" allowing indefinite survival without rejection of grafts of cells has proven to be wrong. Thus, the brain should be regarded as a site where immune responses can occur, albeit in a modified form, and under certain circumstances these are as vigorous as those seen in other peripheral sites. Clinical cell transplant trials have now been performed in Parkinson's disease, Huntington's disease, demyelinating diseases, retinal disorders, stroke, epilepsy, and even deafness, and normally are designed as cell replacement strategies, although implantation of genetically modified cells for supplementation of growth factors has also been tried. In addition, some disorders of the CNS for which cell therapies are being considered have an immunological basis, such as multiple sclerosis, which further complicates the situation. Embryonic neural tissue allografted into the CNS of animals and patients with neurodegenerative conditions survives, makes and receives synapses, and ameliorates behavioral deficits. The use of aborted human tissue is logistically and ethically complicated, which has lead to the search for alternative sources of cells, including xenogeneic tissue, genetically modified cells, and stem cells, all of which can and will induce some level of immune reaction. We review some of the immunological factors involved in transplantation of cells to CNS.
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23.
  • Barker, Roger A, et al. (författare)
  • New approaches for brain repair-from rescue to reprogramming
  • 2018
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 557:7705, s. 329-334
  • Forskningsöversikt (refereegranskat)abstract
    • The ability to repair or promote regeneration within the adult human brain has been envisioned for decades. Until recently, such efforts mainly involved delivery of growth factors and cell transplants designed to rescue or replace a specific population of neurons, and the results have largely been disappointing. New approaches using stem-cell-derived cell products and direct cell reprogramming have opened up the possibility of reconstructing neural circuits and achieving better repair. In this Review we briefly summarize the history of neural repair and then discuss these new therapeutic approaches, especially with respect to chronic neurodegenerative disorders.
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24.
  • Barker, Roger A., et al. (författare)
  • Restorative cell and gene therapies for Parkinson's disease
  • 2023
  • Ingår i: Precision Medicine in Neurodegenerative Disorders, Part II. - 0072-9752 .- 2212-4152. - 9780323855556 ; 193, s. 211-226
  • Bokkapitel (refereegranskat)abstract
    • One of the core pathological features of Parkinson's disease (PD) is the loss of the dopaminergic nigrostriatal pathway which lies at the heart of many of the motor features of this condition as well as some of the cognitive problems. The importance of this pathological event is evident through the clinical benefits that are seen when patients with PD are treated with dopaminergic agents, at least in early-stage disease. However, these agents create problems of their own through stimulation of more intact dopaminergic networks within the central nervous system causing major neuropsychiatric problems including dopamine dysregulation. In addition, over time the nonphysiological stimulation of striatal dopamine receptors by L-dopa containing drugs leads to the genesis of L-dopa-induced dyskinesias that can become very disabling in many cases. As such, there has been much interest in trying to better reconstitute the dopaminergic nigrostriatal pathway using either factors to regrow it, cells to replace it, or gene therapies to restore dopamine transmission in the striatum. In this chapter, we lay out the rationale, history and current status of these different therapies as well as highlighting where the field is heading and what new interventions might come to clinic in the coming years.
  •  
25.
  • Barker, Roger A, et al. (författare)
  • Stem Derived Dopamine Neurons : Will They Replace DBS as the Leading Neurosurgical Treatment for Parkinson's Disease?
  • 2021
  • Ingår i: Journal of Parkinson's Disease. - 1877-718X. ; 11:3, s. 909-917
  • Tidskriftsartikel (refereegranskat)abstract
    • The use of stem cell derived dopamine neurons for treating patients with Parkinson's disease has now evolved to the first in human clinical trials. In this debate, we argue that assuming these trials give positive outcomes that this therapy will supercede DBS as the neurosurgical treatment of choice for PD patients in the future given it is a one-off therapy that repairs a critical pathway in the parkinsonian brain.
  •  
26.
  • Barker, Roger A, et al. (författare)
  • The history and status of dopamine cell therapies for Parkinson's disease
  • Ingår i: BioEssays. - 0265-9247.
  • Forskningsöversikt (refereegranskat)abstract
    • Parkinson's disease (PD) is characterized by the loss of the dopaminergic nigrostriatal pathway which has led to the successful development of drug therapies that replace or stimulate this network pharmacologically. Although these drugs work well in the early stages of the disease, over time they produce side effects along with less consistent clinical benefits to the person with Parkinson's (PwP). As such there has been much interest in repairing this pathway using transplants of dopamine neurons. This work which began 50 years ago this September is still ongoing and has now moved to first in human trials using human pluripotent stem cell-derived dopaminergic neurons. The results of these trials are eagerly awaited although proof of principle data has already come from trials using human fetal midbrain dopamine cell transplants. This data has shown that developing dopamine cells when transplanted in the brain of a PwP can survive long term with clinical benefits lasting decades and with restoration of normal dopaminergic innervation in the grafted striatum. In this article, we discuss the history of this field and how this has now led us to the recent stem cell trials for PwP.
  •  
27.
  • Barker, Roger A., et al. (författare)
  • The need for a standard for informed consent for collection of human fetal material
  • 2022
  • Ingår i: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 17:6, s. 1245-1247
  • Tidskriftsartikel (refereegranskat)abstract
    • The ISSCR has developed the Informed Consent Standards for Human Fetal Tissue Donation and Research to promote uniformity and transparency in tissue donation and collection. This standard is designed to assist those working with and overseeing the regulation of such tissue and reassure the wider community and public.
  •  
28.
  • Birtele, Marcella, et al. (författare)
  • Dual modulation of neuron-specific microRNAs and the REST complex promotes functional maturation of human adult induced neurons
  • 2019
  • Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 593:23, s. 3370-3380
  • Tidskriftsartikel (refereegranskat)abstract
    • Direct neuronal reprogramming can be achieved using different approaches: by expressing neuronal transcription factors or microRNAs; and by knocking down neuronal repressive elements. However, there still exists a high variability in terms of the quality and maturity of the induced neurons obtained, depending on the reprogramming strategy employed. Here, we evaluate different long-term culture conditions and study the effect of expressing the neuronal-specific microRNAs, miR124 and miR9/9*, while reprogramming with forced expression of the transcription factors Ascl1, Brn2, and knockdown of the neuronal repressor REST. We show that the addition of microRNAs supports neuronal maturation in terms of gene and protein expression, as well as in terms of electrophysiological properties.
  •  
29.
  • Birtele, Marcella, et al. (författare)
  • Single-cell transcriptional and functional analysis of dopaminergic neurons in organoid-like cultures derived from human fetal midbrain
  • 2022
  • Ingår i: Development: For advances in developmental biology and stem cells. - : The Company of Biologists. - 1477-9129. ; 149:23
  • Tidskriftsartikel (refereegranskat)abstract
    • Significant efforts are ongoing to develop refined differentiation protocols to generate midbrain dopamine (DA) neurons from pluripotent stem cells (PSCs) for application in disease modeling, diagnostics, drug screening, and cell-based therapies for Parkinson's Disease (PD). An increased understanding of the timing and molecular mechanisms promoting the generation of distinct subtypes of human midbrain DA during development will be essential for guiding future efforts to generate molecularly defined and subtype-specific DA neurons from PSCs. Here, we used droplet-based single-cell RNA sequencing to transcriptionally profile the developing human ventral midbrain (VM) when the DA neurons are generated (6-11 weeks post-conception) and their subsequent differentiation into functional mature DA neurons in primary fetal 3D organoid-like cultures. This approach revealed that 3D cultures are superior to monolayer conditions for their ability to generate and maintain mature DA neurons; hence they have the potential to be used for studying human VM development. These results provide a unique transcriptional profile of the developing human fetal VM and functionally mature human DA neurons, which can be used to guide stem cell-based therapies and disease modeling approaches in PD.
  •  
30.
  • Björklund, Anders, et al. (författare)
  • The basal forebrain cholinergic system as target for cell replacement therapy in Parkinson's disease
  • 2024
  • Ingår i: Brain. - 0006-8950. ; 147:6, s. 1937-1952
  • Forskningsöversikt (refereegranskat)abstract
    • In recent years there has been a renewed interest in the basal forebrain cholinergic system as a target for the treatment of cognitive impairments in patients with Parkinson's disease, due in part to the need to explore novel approaches to treat the cognitive symptoms of the disease and in part to the development of more refined imaging tools that have made it possible to monitor the progressive changes in the structure and function of the basal forebrain system as they evolve over time. In parallel, emerging technologies allowing the derivation of authentic basal forebrain cholinergic neurons from human pluripotent stem cells are providing new powerful tools for the exploration of cholinergic neuron replacement in animal models of Parkinson's disease-like cognitive decline. In this review, we discuss the rationale for cholinergic cell replacement as a potential therapeutic strategy in Parkinson's disease and how this approach can be explored in rodent models of Parkinson's disease-like cognitive decline, building on insights gained from the extensive animal experimental work that was performed in rodent and primate models in the 1980s and 90s. Although therapies targeting the cholinergic system have so far been focused mainly on patients with Alzheimer's disease, Parkinson's disease with dementia may be a more relevant condition. In Parkinson's disease with dementia, the basal forebrain system undergoes progressive degeneration and the magnitude of cholinergic cell loss has been shown to correlate with the level of cognitive impairment. Thus, cell therapy aimed to replace the lost basal forebrain cholinergic neurons represents an interesting strategy to combat some of the major cognitive impairments in patients with Parkinson's disease dementia.
  •  
31.
  • Braun, Emelie, et al. (författare)
  • Comprehensive cell atlas of the first-trimester developing human brain
  • 2023
  • Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 382:6667, s. 172-
  • Tidskriftsartikel (refereegranskat)abstract
    • The adult human brain comprises more than a thousand distinct neuronal and glial cell types, a diversity that emerges during early brain development. To reveal the precise sequence of events during early brain development, we used single-cell RNA sequencing and spatial transcriptomics and uncovered cell states and trajectories in human brains at 5 to 14 postconceptional weeks (pcw). We identified 12 major classes that are organized as ~600 distinct cell states, which map to precise spatial anatomical domains at 5 pcw. We described detailed differentiation trajectories of the human forebrain and midbrain and found a large number of region-specific glioblasts that mature into distinct pre-astrocytes and pre–oligodendrocyte precursor cells. Our findings reveal the establishment of cell types during the first trimester of human brain development.
  •  
32.
  • Bruzelius, Andreas, et al. (författare)
  • Reprogramming human adult fibroblasts into GABAergic interneurons
  • 2021
  • Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Direct reprogramming is an appealing strategy to generate neurons from a somatic cell by forced expression of transcription factors. The generated neurons can be used for both cell replacement strategies and disease modelling. Using this technique, previous studies have shown that γ-aminobutyric acid (GABA) expressing interneurons can be generated from different cell sources, such as glia cells or fetal fibroblasts. Nevertheless, the generation of neurons from adult human fibroblasts, an easily accessible cell source to obtain patient-derived neurons, has proved to be challenging due to the intrinsic blockade of neuronal commitment. In this paper, we used an optimized protocol for adult skin fibroblast reprogramming based on RE1 Silencing Transcription Factor (REST) inhibitn together with a combination of GABAergic fate determinants to convert human adult skin fibroblasts into GABAergic neurons. Our results show a successful conversion in 25 days with upregulation of neuronal gene and protein expression levels. Moreover, we identified specific gene combinations that converted fibroblasts into neurons of a GABAergic intraneuronal fate. Despite the well-known difficulty in converting adult fibroblasts into functional neurons in vitro, we could detect functional maturation in the induced neurons. GABAergic interneurons have relevance for cognitive impairments and brain disorders, such as Alzheimer’s and Parkinson’s diseases, epilepsy, schizophrenia and autism spectrum disorders.
  •  
33.
  • Collins, Lucy M., et al. (författare)
  • Dermal fibroblasts from patients with Parkinson's disease have normal GCase activity and autophagy compared to patients with PD and GBA mutations
  • 2018
  • Ingår i: F1000Research. - : F1000 Research Ltd. - 2046-1402. ; 6
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Recently, the development of Parkinson's disease (PD) has been linked to a number of genetic risk factors, of which the most common is glucocerebrosidase (GBA) mutations. Methods: We investigated PD and Gaucher Disease (GD) patient derived skin fibroblasts using biochemistry assays. Results: PD patient derived skin fibroblasts have normal glucocerebrosidase (GCase) activity, whilst patients with PD and GBA mutations have a selective deficit in GCase enzyme activity and impaired autophagic flux. Conclusions: This data suggests that only PD patients with a GBA mutation have altered GCase activity and autophagy, which may explain their more rapid clinical progression.
  •  
34.
  • Drouin-Ouellet, Janelle, et al. (författare)
  • Age-related pathological impairments in directly reprogrammed dopaminergic neurons derived from patients with idiopathic Parkinson's disease
  • 2022
  • Ingår i: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 17:10, s. 2203-2219
  • Tidskriftsartikel (refereegranskat)abstract
    • We have developed an efficient approach to generate functional induced dopaminergic (DA) neurons from adult human dermal fibroblasts. When performing DA neuronal conversion of patient fibroblasts with idiopathic Parkinson's disease (PD), we could specifically detect disease-relevant pathology in these cells. We show that the patient-derived neurons maintain age-related properties of the donor and exhibit lower basal chaperone-mediated autophagy compared with healthy donors. Furthermore, stress-induced autophagy resulted in an age-dependent accumulation of macroautophagic structures. Finally, we show that these impairments in patient-derived DA neurons leads to an accumulation of phosphorylated alpha-synuclein, the classical hallmark of PD pathology. This pathological phenotype is absent in neurons generated from induced pluripotent stem cells from the same patients. Taken together, our results show that direct neural reprogramming can be used for obtaining patient-derived DA neurons, which uniquely function as a cellular model to study age-related pathology relevant to idiopathic PD.
  •  
35.
  • Drouin-Ouellet, Janelle, et al. (författare)
  • Direct neuronal reprogramming for disease modeling studies using patient-derived neurons : What have we learned?
  • 2017
  • Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 11:SEP
  • Forskningsöversikt (refereegranskat)abstract
    • Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows for the possibility of generating patient-derived neurons. A unique feature of these so-called induced neurons (iNs) is the potential to maintain aging and epigenetic signatures of the donor, which is critical given that many diseases of the CNS are age related. Here, we review the published literature on the work that has been undertaken using iNs to model human brain disorders. Furthermore, as disease-modeling studies using this direct neuronal reprogramming approach are becoming more widely adopted, it is important to assess the criteria that are used to characterize the iNs, especially in relation to the extent to which they are mature adult neurons. In particular: i) what constitutes an iN cell, ii) which stages of conversion offer the earliest/optimal time to assess features that are specific to neurons and/or a disorder and iii) whether generating subtype-specific iNs is critical to the disease-related features that iNs express. Finally, we discuss the range of potential biomedical applications that can be explored using patient-specific models of neurological disorders with iNs, and the challenges that will need to be overcome in order to realize these applications.
  •  
36.
  • Gallo, Valentina, et al. (författare)
  • Parkinson's Disease Case Ascertainment in the EPIC Cohort : The NeuroEPIC4PD Study
  • 2015
  • Ingår i: Neurodegenerative Diseases. - : S. Karger. - 1660-2854 .- 1660-2862. ; 15:6, s. 331-338
  • Tidskriftsartikel (refereegranskat)abstract
    • Background/Aims: Large epidemiological prospective studies represent an important opportunity for investigating risk factors for rare diseases such as Parkinson's disease (PD). Here we describe the procedures we used for ascertaining PD cases in the EPIC (European Prospective Investigation into Cancer and Nutrition) study. Methods: The following three-phase procedure was used: (1) elaboration of a NeuroEPIC4PD template for clinical data collection, (2) identification of all potential PD cases via record linkage and (3) validation of the diagnosis through clinical record revision, in a population of 220,494 subjects recruited in 7 European countries. All cases were labelled with the NeuroEPIC4PD diagnoses of 'definite', 'very likely', 'probable', or 'possible' PD. Results: A total of 881 PD cases were identified, with over 2,741,780 person-years of follow-up (199 definite, 275 very likely, 146 probable, and 261 possible). Of these, 734 were incident cases. The mean age at diagnosis was 67.9 years (SD 9.2) and 458 patients (52.0%) were men. Bradykinesia was the most frequent presenting motor sign (76.5%). Tremor-dominant and akinetic rigid forms of PD were the most common types of PD. A total of 289 patients (32.8%) were dead at the time of the last follow-up. Conclusions: This exercise proved that it is feasible to ascertain PD in large population-based cohort studies and offers a potential framework to be replicated in similar studies.
  •  
37.
  • Griffiths, William J., et al. (författare)
  • The Cerebrospinal Fluid Profile of Cholesterol Metabolites in Parkinson’s Disease and Their Association With Disease State and Clinical Features
  • 2021
  • Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media S.A.. - 1663-4365. ; 13
  • Tidskriftsartikel (refereegranskat)abstract
    • Disordered cholesterol metabolism is linked to neurodegeneration. In this study we investigated the profile of cholesterol metabolites found in the cerebrospinal fluid (CSF) of Parkinson’s disease (PD) patients. When adjustments were made for confounding variables of age and sex, 7α,(25R)26-dihydroxycholesterol and a second oxysterol 7α,x,y-trihydroxycholest-4-en-3-one (7α,x,y-triHCO), whose exact structure is unknown, were found to be significantly elevated in PD CSF. The likely location of the additional hydroxy groups on the second oxysterol are on the sterol side-chain. We found that CSF 7α-hydroxycholesterol levels correlated positively with depression in PD patients, while two presumptively identified cholestenoic acids correlated negatively with depression.
  •  
38.
  • Kaiser, Karol, et al. (författare)
  • MEIS-WNT5A axis regulates development of fourth ventricle choroid plexus
  • 2021
  • Ingår i: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 148:10
  • Tidskriftsartikel (refereegranskat)abstract
    • The choroid plexus (ChP) produces cerebrospinal fluid and forms an essential brain barrier. ChP tissues form in each brain ventricle, each one adopting a distinct shape, but remarkably little is known about the mechanisms underlying ChP development. Here, we show that epithelial WNT5A is crucial for determining fourth ventricle (4V) ChP morphogenesis and size in mouse. Systemic Wnt5a knockout, or forced Wnt5a overexpression beginning at embryonic day 10.5, profoundly reduced ChP size and development. However, Wnt5a expression was enriched in Foxj1-positive epithelial cells of 4V ChP plexus, and its conditional deletion in these cells affected the branched, villous morphology of the 4V ChP. We found that WNT5A was enriched in epithelial cells localized to the distal tips of 4V ChP villi, where WNT5A acted locally to activate non-canonical WNT signaling via ROR1 and ROR2 receptors. During 4V ChP development, MEIS1 bound to the proximal Wnt5a promoter, and gain- and loss-of-function approaches demonstrated that MEIS1 regulated Wnt5a expression. Collectively, our findings demonstrate a dual function of WNT5A in ChP development and identify MEIS transcription factors as upstream regulators of Wnt5a in the 4V ChP epithelium.
  •  
39.
  • Kajtez, Janko, et al. (författare)
  • 3D-Printed Soft Lithography for Complex Compartmentalized Microfluidic Neural Devices
  • 2020
  • Ingår i: Advanced Science. - : Wiley. - 2198-3844. ; 7:16
  • Tidskriftsartikel (refereegranskat)abstract
    • Compartmentalized microfluidic platforms are an invaluable tool in neuroscience research. However, harnessing the full potential of this technology remains hindered by the lack of a simple fabrication approach for the creation of intricate device architectures with high-aspect ratio features. Here, a hybrid additive manufacturing approach is presented for the fabrication of open-well compartmentalized neural devices that provides larger freedom of device design, removes the need for manual postprocessing, and allows an increase in the biocompatibility of the system. Suitability of the method for multimaterial integration allows to tailor the device architecture for the long-term maintenance of healthy human stem-cell derived neurons and astrocytes, spanning at least 40 days. Leveraging fast-prototyping capabilities at both micro and macroscale, a proof-of-principle human in vitro model of the nigrostriatal pathway is created. By presenting a route for novel materials and unique architectures in microfluidic systems, the method provides new possibilities in biological research beyond neuroscience applications.
  •  
40.
  • Kirkeby, Agnete, et al. (författare)
  • Preclinical quality, safety, and efficacy of a human embryonic stem cell-derived product for the treatment of Parkinson's disease, STEM-PD
  • 2023
  • Ingår i: Cell Stem Cell. - 1934-5909. ; 30:10, s. 1299-1314
  • Tidskriftsartikel (refereegranskat)abstract
    • Cell replacement therapies for Parkinson's disease (PD) based on transplantation of pluripotent stem cell-derived dopaminergic neurons are now entering clinical trials. Here, we present quality, safety, and efficacy data supporting the first-in-human STEM-PD phase I/IIa clinical trial along with the trial design. The STEM-PD product was manufactured under GMP and quality tested in vitro and in vivo to meet regulatory requirements. Importantly, no adverse effects were observed upon testing of the product in a 39-week rat GLP safety study for toxicity, tumorigenicity, and biodistribution, and a non-GLP efficacy study confirmed that the transplanted cells mediated full functional recovery in a pre-clinical rat model of PD. We further observed highly comparable efficacy results between two different GMP batches, verifying that the product can be serially manufactured. A fully in vivo-tested batch of STEM-PD is now being used in a clinical trial of 8 patients with moderate PD, initiated in 2022.
  •  
41.
  • Li, Weihua, et al. (författare)
  • Longitudinal functional connectivity changes related to dopaminergic decline in Parkinson's disease
  • 2020
  • Ingår i: NeuroImage: Clinical. - : Elsevier BV. - 2213-1582. ; 28
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated that basal ganglia functional connectivity is altered in Parkinson's disease (PD) as compared to healthy controls. However, such functional connectivity alterations have not been related to the dopaminergic deficits that occurs in PD over time. Objectives: To examine whether functional connectivity impairments are correlated with dopaminergic deficits across basal ganglia subdivisions in patients with PD both cross-sectionally and longitudinally. Methods: We assessed resting-state functional connectivity of basal ganglia subdivisions and dopamine transporter density using 11C-PE2I PET in thirty-four PD patients at baseline. Of these, twenty PD patients were rescanned after 19.9 ± 3.8 months. A seed-based approach was used to analyze resting-state fMRI data. 11C-PE2I binding potential (BPND) was calculated for each participant. PD patients were assessed for disease severity. Results: At baseline, PD patients with greater dopaminergic deficits, as measured with 11C-PE2I PET, showed larger decreases in posterior putamen functional connectivity with the midbrain and pallidum. Reduced functional connectivity of the posterior putamen with the thalamus, midbrain, supplementary motor area and sensorimotor cortex over time were significantly associated with changes in DAT density over the same period. Furthermore, increased motor disability was associated with lower intraregional functional connectivity of the posterior putamen. Conclusions: Our findings suggest that basal ganglia functional connectivity is related to integrity of dopaminergic system in patients with PD. Application of resting-state fMRI in a large cohort and longitudinal scanning may be a powerful tool for assessing underlying PD pathology and its progression.
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42.
  • Lindvall, Olle, et al. (författare)
  • Clinical translation of stem cells in neurodegenerative disorders.
  • 2012
  • Ingår i: Cell Stem Cell. - : Elsevier BV. - 1934-5909. ; 10:2, s. 151-155
  • Tidskriftsartikel (refereegranskat)abstract
    • Stem cells and their derivatives show tremendous potential for treating many disorders, including neurodegenerative diseases. We discuss here the challenges and potential for the translation of stem-cell-based approaches into treatments for Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.
  •  
43.
  • Loane, Clare, et al. (författare)
  • Aberrant nigral diffusion in Parkinson's disease : A longitudinal diffusion tensor imaging study
  • 2016
  • Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 31:7, s. 6-1020
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Measuring microstructure alterations with diffusion tensor imaging in PD is potentially a valuable tool to use as a biomarker for early diagnosis and to track disease progression. Previous studies have reported a specific decrease of nigral fractional anisotropy in PD. However, to date the effect of disease progression on nigral or striatal diffusion indices has not been fully explored.METHODS: We have conducted a cross-sectional and longitudinal diffusion tensor imaging study in 18 early stage, treated PD patients and 14 age-matched controls. PD patients were scanned on 2 occasions OFF medication, 19.3 months apart (standard deviation = 3.1 months). Longitudinal change of regional nigral and striatal measures of fractional anisotropy and mean diffusivity were calculated using a region-of-interest approach.RESULTS: Region-of-interest analysis demonstrated that at baseline, PD patients and controls did not differ in regard to diffusion indices in any region assessed. A significant difference of nigral fractional anisotropy and mean diffusivity between controls and PD patients at follow-up was detected and confirmed with longitudinal analysis within PD patients. Alterations in striatal regions were not detected in either group or over time.CONCLUSION: Our findings indicate that nigral diffusion measure may be a valuable measure of disease progression. In the future, larger longitudinal studies will confirm whether diffusion indices may serve as sensitive and clinically meaningful measures of disease progression in PD. © 2016 International Parkinson and Movement Disorder Society.
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44.
  • Merlevede, Adriaan, et al. (författare)
  • A quantitative model of cellular decision making in direct neuronal reprogramming
  • 2021
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The direct reprogramming of adult skin fibroblasts to neurons is thought to be controlled by a small set of interacting gene regulators. Here, we investigate how the interaction dynamics between these regulating factors coordinate cellular decision making in direct neuronal reprogramming. We put forward a quantitative model of the governing gene regulatory system, supported by measurements of mRNA expression. We found that nPTB needs to feed back into the direct neural conversion network most likely via PTB in order to accurately capture quantitative gene interaction dynamics and correctly predict the outcome of various overexpression and knockdown experiments. This was experimentally validated by nPTB knockdown leading to successful neural conversion. We also proposed a novel analytical technique to dissect system behaviour and reveal the influence of individual factors on resulting gene expression. Overall, we demonstrate that computational analysis is a powerful tool for understanding the mechanisms of direct (neuronal) reprogramming, paving the way for future models that can help improve cell conversion strategies.
  •  
45.
  • Parmar, Malin, et al. (författare)
  • GFORCE-PD still going strong in 2016
  • 2017
  • Ingår i: npj Parkinson's Disease. - : Springer Science and Business Media LLC. - 2373-8057. ; 3
  • Forskningsöversikt (refereegranskat)abstract
    • In 2014, a new initiative was undertaken by groups working on plans for the transplantation of stem-cell-based derived dopaminergic neurons for treating Parkinson’s disease patients. This GForce-PD group held its annual meeting on 18–19 April 2016 in Chicago at Rush University to discuss their progress and the challenges that the translation of this experimental therapy still faces. Over 2 days, the key issues were discussed around the cell lines that will be used, the differentiation protocols, preclinical testing, GMP-adaptation, and cell manufacturing to allow first in human clinical trials, which are anticipated to start in 2017–2018. GForce-PD members also discussed how they can improve outreach and be of better service to the Parkinson's disease (PD) community and help them to make the best possible decisions when pursuing stem cell treatments.
  •  
46.
  • Pircs, Karolina, et al. (författare)
  • Hunting out the autophagic problem in Huntington disease
  • 2022
  • Ingår i: Autophagy. - : Informa UK Limited. - 1554-8627 .- 1554-8635. ; 18:12, s. 3031-3032
  • Tidskriftsartikel (refereegranskat)abstract
    • Huntington disease is an inherited, progressive, incurable neurodegenerative disorder that primarily affects cells in the brain. Although the genetic basis for this condition has been known for nearly 30 years, how this causes disease is still unresolved. Of late there has been increasing evidence suggesting that dysfunction in macroautophagic/autophagic pathways may contribute to cellular dysfunction and death. In our recent work we highlight more precisely how and where this problem might arise in this pathway using directly reprogrammed neurons.
  •  
47.
  • Rittman, Timothy, et al. (författare)
  • Regional expression of the MAPT gene is associated with loss of hubs in brain networks and cognitive impairment in Parkinson disease and progressive supranuclear palsy
  • 2016
  • Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 48, s. 153-160
  • Tidskriftsartikel (refereegranskat)abstract
    • Abnormalities of tau protein are central to the pathogenesis of progressive supranuclear palsy, whereas haplotype variation of the tau gene MAPT influences the risk of Parkinson disease and Parkinson's disease dementia. We assessed whether regional MAPT expression might be associated with selective vulnerability of global brain networks to neurodegenerative pathology. Using task-free functional magnetic resonance imaging in progressive supranuclear palsy, Parkinson disease, and healthy subjects (n = 128), we examined functional brain networks and measured the connection strength between 471 gray matter regions. We obtained MAPT and SNCA microarray expression data in healthy subjects from the Allen brain atlas. Regional connectivity varied according to the normal expression of MAPT. The regional expression of MAPT correlated with the proportionate loss of regional connectivity in Parkinson's disease. Executive cognition was impaired in proportion to the loss of hub connectivity. These effects were not seen with SNCA, suggesting that alpha-synuclein pathology is not mediated through global network properties. The results establish a link between regional MAPT expression and selective vulnerability of functional brain networks to neurodegeneration.
  •  
48.
  • Roussakis, Andreas Antonios, et al. (författare)
  • Parkinson’s disease laterality : a 11C-PE2I PET imaging study
  • 2020
  • Ingår i: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459.
  • Tidskriftsartikel (refereegranskat)abstract
    • Asymmetry of striatal dopaminergic deficits and motor symptoms is a typical characteristic of idiopathic Parkinson’s disease (PD). This study aims to characterise the trend of asymmetry in moderate-stage PD. We performed a 19-month longitudinal study in 27 patients with PET-CT imaging and appropriate clinical assessments. 11C-PE2I non-displaceable binding potential (BPND) was calculated bilaterally for the striatum at baseline and follow-up to estimate the in vivo density of striatal dopamine transporters (DAT). Changes in striatal 11C-PE2I BPND over time were more prominent in the ipsilateral as compared to contralateral side. Changes in MDS-UPDRS-III (motor component of the Movement Disorders Society Unified PD Rating Scale) were not different between the clinically most and least affected body sides. Our data support that the asymmetry in striatal dopaminergic degeneration becomes less prominent in moderate-stage PD. In contrast, during the above period, the asymmetry of motor symptoms was maintained between the clinically most and least affected body sides.
  •  
49.
  • Shrigley, Shelby, et al. (författare)
  • Simple Generation of a High Yield Culture of Induced Neurons from Human Adult Skin Fibroblasts
  • 2018
  • Ingår i: Journal of Visualized Experiments. - : MyJove Corporation. - 1940-087X. ; 132
  • Tidskriftsartikel (refereegranskat)abstract
    • Induced neurons (iNs), the product of somatic cells directly converted to neurons, are a way to obtain patient-derived neurons from tissue thatis easily accessible. Through this route, mature neurons can be obtained in a matter of a few weeks. Here, we describe a straightforward andrapid one-step protocol to obtain iNs from dermal fibroblasts obtained through biopsy samples from adult human donors. We explain each stepof the process, including the maintenance of the dermal fibroblasts, the freezing procedure to build a stock of the cell line, seeding of the cellsfor reprogramming, as well as the culture conditions during the conversion process. In addition, we describe the preparation of glass coverslipsfor electrophysiological recordings, long-term coating conditions, and fluorescence activated cell sorting (FACS). We also illustrate examplesof the results to be expected. The protocol described here is easy to perform and can be applied to human fibroblasts derived from human skinbiopsies from patients with various different diagnoses and ages. This protocol generates a sufficient amount of iNs which can be used for a widearray of biomedical applications, including disease modeling, drug screening, and target validation.
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50.
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