| 1. |
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| 2. |
- Grüning, Björn, et al.
(författare)
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Bioconda: A sustainable and comprehensive software distribution for the life sciences
- 2017
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We present Bioconda (https://bioconda.github.io), a distribution of bioinformatics software for the lightweight, multi-platform and language-agnostic package manager Conda. Currently, Bioconda offers a collection of over 3000 software packages, which is continuously maintained, updated, and extended by a growing global community of more than 200 contributors. Bioconda improves analysis reproducibility by allowing users to define isolated environments with defined software versions, all of which are easily installed and managed without administrative privileges.
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| 3. |
- Aittamaa, Simon
(författare)
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Programming embedded real-time systems : implementation techniques for concurrent reactive objects
- 2011
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- An embedded system is a computer system that is a part of a larger device with hardware and mechanical parts. Such a system often has limited resources (such as processing power, memory, and power) and it typically has to meet hard real-time requirements. Today, as the area of application of embedded systems is constantly increasing, resulting in higher demands on system performance and a growing complexity of embedded software, there is a clear trend towards multi-core and multi-processor systems. Such systems are inherently concurrent, but programming concurrent systems using the traditional abstractions (i.e., explicit threads of execution) has been shown to be both difficult and error-prone. The natural solution is to raise the abstraction level and make concurrency implicit, in order to aid the programmer in the task of writing correct code. However, when we raise the abstraction level, there is always an inherent cost. In this thesis we consider one possible concurrency model, the concurrent reactive object approach that offers implicit concurrency at the object level. This model has been implemented in the programming language Timber, which primarily targets development of real-time systems. It is also implemented in TinyTimber, a subset of the C language closely matching Timber’s execution model. We quantify various costs of a TinyTimber implementation of the model (such as context switching and message passing overheads) on a number of hardware platforms and compare them to the costs of the more common thread-based approach. We then demonstrate how some of these costs can be mitigated using stack resource policy. On a separate track, we present a feasibility test for garbage collection in a reactive real-time system with automatic memory management, which is a necessary component for verification of correctness of a real-time system implemented in Timber
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| 4. |
- Brinkmalm, Gunnar, et al.
(författare)
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A Parallel Reaction Monitoring Mass Spectrometric Method for Analysis of Potential CSF Biomarkers for Alzheimer's Disease.
- 2018
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Ingår i: Proteomics. Clinical applications. - : Wiley. - 1862-8354 .- 1862-8346. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to develop and evaluate a parallel reaction monitoring mass spectrometry (PRM-MS) assay consisting of a panel of potential protein biomarkers in cerebrospinal fluid (CSF).Thirteen proteins were selected based on their association with neurodegenerative diseases and involvement in synaptic function, secretory vesicle function, or innate immune system. CSF samples were digested and two to three peptides per protein were quantified using stable isotope-labeled peptide standards.Coefficients of variation were generally below 15%. Clinical evaluation was performed on a cohort of 10 patients with Alzheimer's disease (AD) and 15 healthy subjects. Investigated proteins of the granin family exhibited the largest difference between the patient groups. Secretogranin-2 (p<0.005) and neurosecretory protein VGF (p<0.001) concentrations were lowered in AD. For chromogranin A, two of three peptides had significantly lowered AD concentrations (p<0.01). The concentrations of the synaptic proteins neurexin-1 and neuronal pentraxin-1, as well as neurofascin were also significantly lowered in AD (p<0.05). The other investigated proteins, β2-microglobulin, cystatin C, amyloid precursor protein, lysozyme C, neurexin-2, neurexin-3, and neurocan core protein, were not significantly altered.PRM-MS of protein panels is a valuable tool to evaluate biomarker candidates for neurodegenerative disorders.
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| 5. |
- Brockmann, K., et al.
(författare)
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Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson's disease and dementia with Lewy bodies
- 2021
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- The clinicopathological heterogeneity in Lewy-body diseases (LBD) highlights the need for pathology-driven biomarkers in-vivo. Misfolded alpha-synuclein (alpha-Syn) is a lead candidate based on its crucial role in disease pathophysiology. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has recently shown high sensitivity and specificity for the detection of misfolded alpha-Syn in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this study we performed the CSF RT-QuIC assay in 236 PD and 49 DLB patients enriched for different genetic forms with mutations in GBA, parkin, PINK1, DJ1, and LRRK2. A subgroup of 100 PD patients was also analysed longitudinally. We correlated kinetic seeding parameters of RT-QuIC with genetic status and CSF protein levels of molecular pathways linked to alpha-Syn proteostasis. Overall, 85% of PD and 86% of DLB patients showed positive RT-QuIC alpha-Syn seeding activity. Seeding profiles were significantly associated with mutation status across the spectrum of genetic LBD. In PD patients, we detected positive alpha-Syn seeding in 93% of patients carrying severe GBA mutations, in 78% with LRRK2 mutations, in 59% carrying heterozygous mutations in recessive genes, and in none of those with bi-allelic mutations in recessive genes. Among PD patients, those with severe GBA mutations showed the highest seeding activity based on RT-QuIC kinetic parameters and the highest proportion of samples with 4 out of 4 positive replicates. In DLB patients, 100% with GBA mutations showed positive alpha-Syn seeding compared to 79% of wildtype DLB. Moreover, we found an association between alpha-Syn seeding activity and reduced CSF levels of proteins linked to alpha-Syn proteostasis, specifically lysosome-associated membrane glycoprotein 2 and neurosecretory protein VGF. These findings highlight the value of alpha-Syn seeding activity as an in-vivo marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting alpha-Syn.
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| 6. |
- Jufvas, Åsa, et al.
(författare)
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Global differences in specific histone H3 methylation are associated with overweight and type 2 diabetes.
- 2013
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Ingår i: Clinical Epigenetics. - : BioMed Central. - 1868-7083 .- 1868-7075. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Epidemiological evidence indicates yet unknown epigenetic mechanisms underlying a propensity for overweight and type 2 diabetes. We analyzed the extent of methylation at lysine 4 and lysine 9 of histone H3 in primary human adipocytes from 43 subjects using modification-specific antibodies.RESULTS: The level of lysine 9 dimethylation was stable, while adipocytes from type 2 diabetic and non-diabetic overweight subjects exhibited about 40% lower levels of lysine 4 dimethylation compared with cells from normal-weight subjects. In contrast, trimethylation at lysine 4 was 40% higher in adipocytes from overweight diabetic subjects compared with normal-weight and overweight non-diabetic subjects. There was no association between level of modification and age of subjects.CONCLUSIONS: The findings define genome-wide molecular modifications of histones in adipocytes that are directly associated with overweight and diabetes, and thus suggest a molecular basis for existing epidemiological evidence of epigenetic inheritance.
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| 7. |
- Kildal, Per-Simon, 1951, et al.
(författare)
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EuCAP 2013 in Gothenburg, Sweden: "An Impressive Success"
- 2013
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Ingår i: IEEE Antennas and Propagation Magazine. - 1045-9243. ; 55:3, s. 276-278
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- “Impressive Success” is, of course, not our words, but we take them to our hearts and want to share them with the readers of the Antennas and Propagation Magazine. And, yes, we were also satisfied with the arrangements of EuCAP 2013. The SCC venue (Swedish Exhibition & Congress Center) was very modern and practical; the collaboration with EurAAP as well as the professional conference organizers was to the satisfaction of all of us. Most important is all the positive feedback we have received from the attendees, who “even” were satisfied with the food provided by the venue restaurant, which was of high quality (the “even” refers to the fact that food is not what Sweden is most world-famous for). According to the EurAAP Chair: “EuCAP is after the Gothenburg edition, a top quality and worldwide appreciated conference.”
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| 8. |
- Larena, Maximilian, et al.
(författare)
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Multiple migrations to the Philippines during the last 50,000 years
- 2021
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 118:13
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Tidskriftsartikel (refereegranskat)abstract
- Island Southeast Asia has recently produced several surprises regarding human history, but the region's complex demography remains poorly understood. Here, we report similar to 2.3 million genotypes from 1,028 individuals representing 115 indigenous Philippine populations and genome-sequence data from two similar to 8,000-y-old individuals from Liangdao in the Taiwan Strait. We show that the Philippine islands were populated by at least five waves of human migration: initially by Northern and Southern Negritos (distantly related to Australian and Papuan groups), followed by Manobo, Sama, Papuan, and Cordilleran-related populations. The ancestors of Cordillerans diverged from indigenous peoples of Taiwan at least similar to 8,000 y ago, prior to the arrival of paddy field rice agriculture in the Philippines similar to 2,500 y ago, where some of their descendants remain to be the least admixed East Asian groups carrying an ancestry shared by all Austronesian-speaking populations. These observations contradict an exclusive "out-of-Taiwan" model of farming-language-people dispersal within the last four millennia for the Philippines and Island Southeast Asia. Sama-related ethnic groups of southwestern Philippines additionally experienced some minimal South Asian gene flow starting similar to 1,000 y ago. Lastly, only a few lowlanders, accounting for <1% of all individuals, presented a low level of West Eurasian admixture, indicating a limited genetic legacy of Spanish colonization in the Philippines. Altogether, our findings reveal a multilayered history of the Philippines, which served as a crucial gateway for the movement of people that ultimately changed the genetic landscape of the Asia-Pacific region.
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| 9. |
- Lerche, S., et al.
(författare)
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CSF Protein Level of Neurotransmitter Secretion, Synaptic Plasticity, and Autophagy in PD and DLB
- 2021
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 36:11, s. 2595-2604
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Tidskriftsartikel (refereegranskat)abstract
- Background Molecular pathways associated with alpha-synuclein proteostasis have been detected in genetic studies and in cell models and include autophagy, ubiquitin-proteasome system, mitochondrial homeostasis, and synaptic plasticity. However, we lack biomarkers that are representative for these pathways in human biofluids. Objective The objective of this study was to evaluate CSF protein profiles of pathways related to alpha-synuclein proteostasis. Methods We assessed CSF protein profiles associated with neurotransmitter secretion, synapse plasticity, and autophagy in 2 monocentric cohorts with alpha-synucleinopathy (385 PD patients and 67 DLB patients). We included 80 PD patients and 17 DLB patients with variants in the glucocerebrosidase gene to serve as proxy for accelerated alpha-synuclein pathology with pronounced clinical trajectories. Results (1) Proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy were lower in PD and DLB patients compared with healthy controls. (2) These patterns were more pronounced in DLB than in PD patients, accentuated by GBA variant status in both entities. (3) CSF levels of these proteins were positively associated with CSF levels of total alpha-synuclein, with lower levels of proteostasis proteins related to lower levels of total alpha-synuclein. (4) These findings could be confirmed longitudinally. PD patients with low CSF profiles of proteostasis proteins showed lower CSF levels of alpha-synuclein longitudinally compared with PD patients with a normal proteostasis profile. Conclusion CSF proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy might serve as biomarkers related to alpha-synuclein proteostasis in PD and DLB. (c) 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
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| 10. |
- Lowe, A. J., et al.
(författare)
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Cerebrospinal fluid endo-lysosomal proteins as potential biomarkers for Huntington's disease
- 2020
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 15:8
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Tidskriftsartikel (refereegranskat)abstract
- Molecular markers derived from cerebrospinal fluid (CSF) represent an accessible means of exploring the pathobiology of Huntington's disease (HD) in vivo. The endo-lysosomal/autophagy system is dysfunctional in HD, potentially contributing to disease pathogenesis and representing a potential target for therapeutic intervention. Several endo-lysosomal proteins have shown promise as biomarkers in other neurodegenerative diseases; however, they have yet to be fully explored in HD. We performed parallel reaction monitoring mass spectrometry analysis (PRM-MS) of multiple endo-lysosomal proteins in the CSF of 60 HD mutation carriers and 20 healthy controls. Using generalised linear models controlling for age and CAG, none of the 18 proteins measured displayed significant differences in concentration between HD patients and controls. This was affirmed by principal component analysis, in which no significant difference across disease stage was found in any of the three components representing lysosomal hydrolases, binding/transfer proteins and innate immune system/peripheral proteins. However, several proteins were associated with measures of disease severity and cognition: most notably amyloid precursor protein, which displayed strong correlations with composite Unified Huntington's Disease Rating Scale, UHDRS Total Functional Capacity, UHDRS Total Motor Score, Symbol Digit Modalities Test and Stroop Word Reading. We conclude that although endo-lysosomal proteins are unlikely to have value as disease state CSF biomarkers for Huntington's disease, several proteins demonstrate associations with clinical severity, thus warranting further, targeted exploration and validation in larger, longitudinal samples.
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| 11. |
- Minta, Karolina, et al.
(författare)
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Quantification of total apolipoprotein E and its isoforms in cerebrospinal fluid from patients with neurodegenerative diseases
- 2020
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Ingår i: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background The human APOE gene, which codes for apolipoprotein E (apoE), has three major polymorphic alleles: epsilon 2, epsilon 3, and epsilon 4 that give rise to amino acid substitutions. APOE-epsilon 4 is a strong risk factor of sporadic Alzheimer's disease (AD) but the reason why is still unknown despite intense research for more than 20 years. The aim of the study was to investigate if the concentrations of total apoE and the specific apoE isoforms in cerebrospinal fluid (CSF) differ between various neurodegenerative diseases and control individuals, as well as among the APOE genotypes. Methods Quantification of total apoE and specific apoE isoforms (E2, E3, and E4) in CSF was performed using high-resolution parallel reaction monitoring mass spectrometry. In total, 1820 individuals were involved in the study including clinically diagnosed AD patients (n = 228), cognitively unimpaired (CU) patients (n = 896), and patients with other neurodegenerative disorders (n = 696). Follow-up data was available for 100 individuals, assessed at two time points. Subjects were dichotomized based on an A beta(42/40) CSF concentration ratio cut-off into A beta positive (A beta+, < 0.091) and A beta negative (A beta-, > 0.091) groups. Results Even though there was a significant increase of total apoE in the amyloid beta-positive (A beta+) group compared with amyloid beta-negative (A beta-) individuals (p < 0.001), the magnitude of the effect was very small (AUC = 0.55). Moreover, CSF total apoE concentrations did not differ between A beta- CU controls and clinically diagnosed AD patients. There was a difference in concentration between isoforms in heterozygous individuals in an isoform-dependent manner (E2 < E3 < E4) (p < 0.001, AUC = 0.64-0.69), and these associations remained when dichotomizing the samples into A beta+ and A beta- groups (p < 0.01, AUC = 0.63-0.74). In the cohort with follow-up samples, neither total apoE nor isoform-specific apoE concentrations differed between the two time points (p > 0.05). Conclusions The results indicate that neither the concentrations of total apoE nor the different apoE isoforms in CSF are associated with APOE-epsilon 4 carrier status, A beta status, or clinical dementia diagnoses.
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| 12. |
- Nilsson, Johanna, 1993, et al.
(författare)
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Cerebrospinal fluid biomarker panel for synaptic dysfunction in Alzheimer's disease
- 2021
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Ingår i: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. - : Wiley. - 2352-8729. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Synaptic dysfunction and degeneration is one of the earliest events in Alzheimer's disease (AD) and the best correlate of cognitive decline. Thus, identification and validation of biomarkers reflecting synaptic degeneration to be used as prognostic biomarkers are greatly needed. Method Solid-phase extraction and parallel reaction monitoring mass spectrometry were used to quantify 17 synaptic proteins in CSF, in two cross-sectional studies including AD (n = 52) and controls (n = 37). Results Increased concentrations of beta-synuclein, gamma-synuclein, neurogranin, phosphatidylethanolamine-binding protein 1, and 14-3-3 proteins were observed in AD patients compared to controls, while neuronal pentraxin-2 and neuronal pentraxin receptor were decreased. Discussion We have established a method with a novel panel of synaptic proteins as biomarkers of synaptic dysfunction. The results indicate that several of the proteins included in the panel may serve as synaptic biomarkers for AD.
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| 13. |
- Sandin, Linnea, et al.
(författare)
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The Luminescent Conjugated Oligothiophene h-FTAA Attenuates the Toxicity of Different A beta Species
- 2021
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 60:37, s. 2773-2780
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Tidskriftsartikel (refereegranskat)abstract
- The prevailing opinion is that prefibrillar beta-amyloid (A beta) species, rather than end-stage amyloid fibrils, cause neuronal dysfunction in Alzheimers disease, although the mechanisms behind A beta neurotoxicity remain to be elucidated. Luminescent conjugated oligothiophenes (LCOs) exhibit spectral properties upon binding to amyloid proteins and have previously been reported to change the toxicity of A beta(1- 42) and prion protein. In a previous study, we showed that an LCO, pentamer formyl thiophene acetic acid (p-FTAA), changed the toxicity of A beta(1-42). Here we investigated whether an LCO, heptamer formyl thiophene acetic acid (h-FTAA), could change the toxicity of A beta(1-42) by comparing its behavior with that of p-FTAA. Moreover, we investigated the effects on toxicity when A ss with the Arctic mutation (A beta Arc) was aggregated with both LCOs. Cell viability assays on SH-SY5Y neuroblastoma cells demonstrated that h-FTAA has a stronger impact on A beta(1-42) toxicity than does p-FTAA. Interestingly, h-FTAA, but not p-FTAA, rescued the A beta(Arc)-mediated toxicity. Aggregation kinetics and binding assay experiments with A beta(1-42) and A beta(Arc) when aggregated with both LCOs showed that h-FTAA and p-FTAA either interact with different species or affect the aggregation in different ways. In conclusion, h-FTAA protects against A beta(1-42) and A beta(Arc) toxicity, thus showing h-FTAA to be a useful tool for improving our understanding of the process of A beta aggregation linked to cytotoxicity.
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| 14. |
- Sjödin, Simon, et al.
(författare)
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APLP1 as a cerebrospinal fluid biomarker for gamma-secretase modulator treatment
- 2015
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Alzheimer's disease brains are characterized by extracellular plaques containing the aggregated amyloid beta(42) (A beta(42)) peptide and intraneuronal tangles containing hyperphosphorylated tau. A beta(42) is produced by sequential processing of the amyloid precursor protein (APP) by beta-secretase followed by gamma-secretase. Substantial efforts have been put into developing pharmaceuticals preventing the production or increasing the clearance of A beta(42). However, treatments inhibiting gamma- secretase have proven disappointing due to off-target effects. To circumvent these effects, gamma-secretase modulators (GSMs) have been developed, which rather than inhibiting gamma- secretase shift its preference into producing less aggregation-prone shorter A beta peptides. Belonging to the same family of proteins as APP, amyloid-like protein 1 (APLP1) is also a substrate for gamma-secretase. Herein we investigated whether the GSM E2012 affects APLP1 processing in the central nervous system by measuring APLP1 peptide levels in cerebrospinal fluid (CSF) before and after E2012 treatment in dogs. Methods: An in-house monoclonal APLP1 antibody, AP1, was produced and utilized for immunopurification of APLP1 from human and dog CSF in a hybrid immuno-affinity mass spectrometric method. Seven dogs received a single dose of 20 or 80 mg/kg of E2012 in a randomized cross-over design and CSF was collected prior to and 4, 8 and 24 hours after dosing. Results: We have identified 14 CSF APLP1 peptides in humans and 12 CSF APLP1 peptides in dogs. Of these, seven were reproducibly detectable in dogs who received E2012. We found a dose-dependent relative increase of the CSF peptides APLP1 beta 17, 1 beta 18 and 1 beta 28 accompanied with a decrease of 1 beta 25 and 1 beta 27 in response to E2012 treatment. All peptides reverted to baseline over the time of sample collection. Conclusion: We show an in vivo effect of the GSM E2012 on the processing of APLP1 which is measurable in CSF. These data suggest that APLP1 peptides may be used as biomarkers to monitor drug effects of GSMs on gamma-secretase processing in clinical trials. However, this requires further investigation in larger cohorts, including studies in man.
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| 15. |
- Sjödin, Simon, et al.
(författare)
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Endo-lysosomal proteins and ubiquitin CSF concentrations in Alzheimer's and Parkinson's disease
- 2019
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Ingår i: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Increasing evidence implicates dysfunctional proteostasis and the involvement of the autophagic and endo-lysosomal system and the ubiquitin-proteasome system in neurodegenerative diseases. In Alzheimer's disease (AD), there is an accumulation of autophagic vacuoles within the neurons. In Parkinson's disease (PD), susceptibility has been linked to genes encoding proteins involved in autophagy and lysosomal function, as well as mutations causing lysosomal disorders. Furthermore, both diseases are characterized by the accumulation of protein aggregates. Methods Proteins associated with endocytosis, lysosomal function, and the ubiquitin-proteasome system were identified in the cerebrospinal fluid (CSF) and targeted by combining solid-phase extraction and parallel reaction monitoring mass spectrometry. In total, 50 peptides from 18 proteins were quantified in three cross-sectional cohorts including AD (N = 61), PD (N = 21), prodromal AD (N = 10), stable mild cognitive impairment (N = 15), and controls (N = 68). Results A pilot study, including subjects selected based on their AD CSF core biomarker concentrations, showed increased concentrations of several targeted proteins in subjects with core biomarker levels indicating AD pathology compared to controls. Next, in a clinically characterized cohort, lower concentrations in CSF of proteins in PD were found compared to subjects with prodromal AD. Further investigation in an additional clinical study again revealed lower concentrations in CSF of proteins in PD compared to controls and AD. Conclusion In summary, significantly different peptide CSF concentrations were identified from proteins AP2B1, C9, CTSB, CTSF, GM2A, LAMP1, LAMP2, TCN2, and ubiquitin. Proteins found to have altered concentrations in more than one study were AP2B1, CTSB, CTSF, GM2A, LAMP2, and ubiquitin. Interestingly, given the genetic implication of lysosomal function in PD, we did identify the CSF concentrations of CTSB, CTSF, GM2A, and LAMP2 to be altered. However, we also found differences in proteins associated with endocytosis (AP2B1) and the ubiquitin-proteasome system (ubiquitin). No difference in any peptide CSF concentration was found in clinically characterized subjects with AD compared to controls. In conclusion, CSF analyses of subjects with PD suggest a general lysosomal dysfunction, which resonates well with recent genetic findings, while such changes are minor or absent in AD.
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| 16. |
- Sjödin, Simon
(författare)
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Evaluation of the Endo-Lysosomal System and the Ubiquitin-Proteasome System in Neurodegenerative Diseases
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neurodegeneration is the process of neuronal cell loss where the symptoms will reflect the regions affected. Neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD) and frontotemporal dementia (FTD) are all characterised by an accumulation of protein aggregates suggesting impaired production or turnover of these proteins. Hence, dysfunctional proteostasis is implicated in neurodegenerative disorders. In AD, there is a decreased turnover of endocytic and autophagic vesicles and an accumulation of endo-lysosomal proteins and ubiquitin in brain tissue. Lysosomal dysfunction has been indicated in PD by the link of disease risk and genetic alterations associated with lysosomal storage disorders as well as by decreased expression of lysosomal proteins in disease afflicted regions. Disease causing mutations and genetic risk factors in FTD suggest altered function of the autophagic and endo-lysosomal system to be involved in the pathogenesis. The aim of this thesis was to examine dysfunctional proteostasis in neurodegenerative diseases by developing assays to monitor proteins from the autophagic and endo-lysosomal system and the ubiquitin-proteasome system in human cerebrospinal fluid (CSF). Proteins from the endo-lysosomal system and the ubiquitin-proteasome system have been identified and quantified in CSF using mass spectrometry (MS)-based proteomics. Principally, three methods have been developed; 1) lysosomal membrane protein LAMP2 was purified from CSF by immunoprecipitation followed by tryptic digestion and quantification by liquid chromatography (LC) and parallel reaction monitoring MS (PRM-MS); 2) full length ubiquitin was isolated from CSF by solid-phase extraction (SPE) followed by quantification by LC PRM-MS; and 3) finally, a panel of endo-lysosomal proteins, e.g., LAMP2, and ubiquitin, were analysed using tryptic digestion, peptide isolation by SPE and quantification by LC PRM-MS. CSF samples from cohorts including subjects with AD, PD, clinical FTD subtypes and FTD mutation carriers, as well as controls, were analysed with the developed assays. In AD the CSF levels of several endo-lysosomal proteins, including LAMP2, were elevated compared to controls. CSF ubiquitin was also found to be elevated in AD compared to controls. In contrast, CSF levels of endo-lysosomal proteins and ubiquitin in PD were found to be decreased. Investigation in clinical subtypes of FTD and mutation carriers showed limited alterations in the CSF levels of endo-lysosomal proteins, suggesting dysfunctional proteostasis not to be readily detected in CSF in FTD. Our results showing altered CSF levels of proteins involved in proteostasis in AD and PD might indicate pathological alterations in the autophagic and endo-lysosomal system and the ubiquitin-proteasome system. Although further studies are needed, CSF ubiquitin in AD and endo-lysosomal proteins and ubiquitin in PD might serve as potential biomarkers in these disorders.
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| 17. |
- Sjödin, Simon, et al.
(författare)
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Mass Spectrometric Analysis of Cerebrospinal Fluid Ubiquitin in Alzheimer's Disease and Parkinsonian Disorders
- 2017
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Ingår i: Proteomics - Clinical Applications. - : Wiley. - 1862-8346 .- 1862-8354. ; 11:11-12
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Dysfunctional proteostasis, with decreased protein degradation and an accumulation of ubiquitin into aggregated protein inclusions, is a feature of neurodegenerative diseases. Identifying new potential biomarkers in cerebrospinal fluid (CSF) reflecting this process could contribute important information on pathophysiology. Experimental design: A developed method combining SPE and PRM-MS is employed to monitor the concentration of ubiquitin in CSF from subjects with Alzheimer's disease (AD), Parkinson's disease (PD), and progressive supranuclear palsy (PSP). Four independent cross-sectional studies are conducted, studies 1–4, including controls (n = 86) and participants with AD (n = 60), PD (n = 15), and PSP (n = 11). Results: The method shows a repeatability and intermediate precision not exceeding 6.1 and 7.9%, respectively. The determined LOD is 0.1 nm and the LOQ range between 0.625 and 80 nm. The CSF ubiquitin concentration is 1.2–1.5-fold higher in AD patients compared with controls in the three independent AD-control studies (Study 1, p < 0.001; Study 2, p < 0.001; and Study 3, p = 0.003). In the fourth study, there is no difference in PD or PSP, compared to controls. Conclusion and clinical relevance: CSF ubiquitin may reflect dysfunctional proteostasis in AD. The described method can be used for further exploration of ubiquitin as a potential biomarker in neurodegenerative diseases.
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| 18. |
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| 19. |
- Swift, I. J., et al.
(författare)
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Differential patterns of lysosomal dysfunction are seen in the clinicopathological forms of primary progressive aphasia
- 2024
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Ingår i: Journal of Neurology. - 0340-5354. ; 271:3, s. 1277-1285
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Tidskriftsartikel (refereegranskat)abstract
- Increasing evidence implicates endo-lysosomal dysfunction in frontotemporal dementia (FTD). 18 proteins were quantified using a mass spectrometry assay panel in the cerebrospinal fluid of 36 people with the language variant of FTD, primary progressive aphasia (PPA) (including 13 with non-fluent variant (nfvPPA), 11 with semantic variant (svPPA), and 12 with logopenic variant (lvPPA)) and 19 healthy controls. The concentrations of the cathepsins (B, D, F, L1, and Z) as well as AP-2 complex subunit beta, ganglioside GM2 activator, beta-hexosaminidase subunit beta, tissue alpha l-fucosidase, and ubiquitin were decreased in nfvPPA compared with controls. In contrast, the concentrations of amyloid beta A4 protein, cathepsin Z, and dipeptidyl peptidase 2 were decreased in svPPA compared with controls. No proteins were abnormal in lvPPA. These results indicate a differential alteration of lysosomal proteins in the PPA variants, suggesting those with non-Alzheimer's pathologies are more likely to show abnormal lysosomal function.
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| 20. |
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| 21. |
- van Daalen, Kim R., et al.
(författare)
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The 2024 Europe report of the lancet countdown on health and climate change : unprecedented warming demands unprecedented action
- 2024
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Ingår i: The Lancet Public Health. - : Elsevier. - 2468-2667. ; 9:7, s. e495-e522
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Forskningsöversikt (refereegranskat)abstract
- Record-breaking temperatures were recorded across the globe in 2023. Without climate action, adverse climate-related health impacts are expected to worsen worldwide, affecting billions of people. Temperatures in Europe are warming at twice the rate of the global average, threatening the health of populations across the continent and leading to unnecessary loss of life. The Lancet Countdown in Europe was established in 2021, to assess the health profile of climate change aiming to stimulate European social and political will to implement rapid health-responsive climate mitigation and adaptation actions. In 2022, the collaboration published its indicator report, tracking progress on health and climate change via 33 indicators and across five domains.This new report tracks 42 indicators highlighting the negative impacts of climate change on human health, the delayed climate action of European countries, and the missed opportunities to protect or improve health with health-responsive climate action. The methods behind indicators presented in the 2022 report have been improved, and nine new indicators have been added, covering leishmaniasis, ticks, food security, health-care emissions, production and consumption-based emissions, clean energy investment, and scientific, political, and media engagement with climate and health. Considering that negative climate-related health impacts and the responsibility for climate change are not equal at the regional and global levels, this report also endeavours to reflect on aspects of inequality and justice by highlighting at-risk groups within Europe and Europe's responsibility for the climate crisis.
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