| 1. |
- Boman, Andrea, 1978-
(författare)
-
Lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease
- 2015
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The pre-symptomatic stage of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) occurs several decades before the clinical onset. Changes in the lysosomal network, i.e. the autophagosomal, endosomal and lysosomal vesicular system, are among the first alterations observed. There are currently no treatments to slow or cure neurodegenerative diseases, and there is a great need for discovery of treatment targets in cellular pathways where pathology pre-dates the neuronal death. It is also crucial to be able to diagnose neurodegenerative diseases earlier, both to enable early intervention treatment and aid in selecting clinical trial populations before the patient has widespread pathology.This thesis aims at investigating the potential of lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease.A targeted search for lysosomal network proteins was performed in cerebrospinal fluid (CSF) from AD patients, and seven proteins: early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), lysozyme, microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were elevated. The levels of EEA1, LAMP-1, LAMP-2, LC3, lysozyme and Rab3 were also measured in CSF from parkinsonian syndrome patients: PD, clinically diagnosed 4-repeat tauopathy, pathologically confirmed corticobasal degeneration (CBD) and pathologically confirmed progressive supranuclear palsy (PSP) patients. LAMP-1 and LAMP-2 were decreased in PD. LC3 and lysozyme levels were increased in 4-repeat tauopathy patients. EEA1 was decreased and lysozyme increased in PSP, and LAMP-1, LAMP-2, LC3 and lysozyme were increased in CBD. The lysosomal network proteins had different CSF protein profiles in all the parkinsonian syndromes, as well as in AD. It should be emphasized that only a select few of the lysosomal network proteins were observed to be changed, rather than a general change in lysosomal network proteins, which implicates the involvement of these seven proteins in specific pathological processes. The most interesting candidates, LAMP-2 and lysozyme, were selected for further study for their involvement in the pathology of AD.Lysozyme was found to co-localise with Aβ plaques in AD patients and overexpression prolonged survival and improved the activity in a Drosophila model of AD. Lysozyme was found to alter the aggregation pathway of Aβ1-42, to counteract the formation of toxic Aβ species and to protect from Aβ1-42 induced cell toxicity. Aβ1-42 in turn was found to increase the expression of lysozyme in both neuronal and glial cells. These data suggest that lysozyme levels rise in AD as a compensatory response which is protective against Aβ associated toxicity.LAMP-2 mRNA and protein were found increased in brain areas relevant for AD pathology and various cellular models showed complex involvement of LAMP-2 in Aβ related pathology, with extensive crosstalk between LAMP-2 and Aβ. Exposure to oligomeric Aβ1-42 caused an upregulation of LAMP-2 and in turn, overexpression of LAMP-2 caused a reduction in secreted levels of Aβ1-42, as well as changing the generation pattern of Aβ and affecting clearance and secretion of Aβ1-42. These data indicate that the increased levels of LAMP-2 in AD could be an attempt to regulate Aβ generation and secretion.In summary, this thesis reports that utilising lysosomal network proteins as biomarkers and novel therapeutic targets for neurodegenerative diseases holds great promise.
|
|
| 2. |
|
|
| 3. |
- Hansson, Oskar
(författare)
-
Neuronal Cell Death and Restoration in the Basal Ganglia: Implications for Huntington's and Parkinson's diseases
- 2001
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Huntington's disease (HD) is a hereditary neurodegenerative disorder presenting with chorea, dementia and extensive striatal neuronal death. The mechanism through which the widely expressed mutant huntingtin mediates striatal neurotoxicity is unknown. Excitotoxicity, i.e. calcium-dependent cell death induced by activation of NMDA receptors, has been hypothesized to play an important role in HD. Our aim was to investigate whether mutant huntingtin alters the susceptibility of striatal neurons to NMDA receptor-induced death in vivo. In 1996 transgenic HD mice that express the N-terminal fragment of mutant huntingtin (R6/1 and R6/2 mice) were generated. Surprisingly, we found that R6 HD mice are totally resistant to striatal lesions caused by the NMDA receptor agonist quinolinic acid, and partially resistant to the mitochondrial toxin malonate. The resistance develops gradually with age in both R6/1 and R6/2 mice, and it occurs earlier in R6/2 (155 CAG repeats) than in R6/1 (115 CAG repeats) mice. Therefore, the resistance to excitotoxins in the striatum is dependent on both the CAG repeat length and the age of the transgenic mice. However, there is a trend towards increased susceptibility to striatal excitotoxicity in very young R6/1 mice. The development of the resistance correlates with the appearance of nuclear huntingtin inclusions in R6 mice. Interestingly, NMDA receptor-induced current and calcium influx in striatal R6 HD neurons are not altered. However, R6 HD neurons have a better capacity to handle the cytoplasmic calcium overload following NMDA receptor activation. We hypothesize that the N-terminal fragment of mutant huntingtin induces a sublethal grade of excitotoxicity. This might cause an adaptation of R6 HD neurons to excitotoxic stress. In 1999 transgenic HD mice were generated that express full-length mutant huntingtin. Interestingly, we found that these mice are more susceptible to NMDA receptor-induced striatal toxicity, indicating that excitotoxicity might play an important role in HD. Parkinson's disease (PD) is a neurodegenerative disorder characterized by rigidity, tremor, bradykinesia and depletion of striatal dopamine. Transplantation of dopaminergic neurons to the striatum can efficiently reduce symptoms in PD patients. However, the majority of implanted dopamine neurons die, at least in part through apoptosis. We found that treatment with the caspase inhibitor ac-YVAD-cmk increases the survival of dopaminergic neurons grafted to hemiparkinsonian rats, and thereby significantly improves functional recovery. When ac-YVAD-cmk is combined with the lazaroid tirilazad mesylate the two drugs had an additive effect on the survival. This indicates that both caspases and free radicals are important mediators of the death of transplanted dopaminergic neurons. In addition, we showed that the calcineurin inhibitors FK506 and cyclosporin A improve the survival of grafted dopaminergic neurons. In summary, R6 HD mice develop a resistance to striatal excitotoxicity over time, even though there is a trend for increased sensitivity at early ages. HD mice expressing full-length mutant huntingtin are more susceptible to excitotoxicity in the striatum, indicating that alterations in NMDA receptor-induced death may play a major role in HD. Furthermore, we found that inhibition of caspases, lipid peroxidation, and calcineurin increase the survival of dopaminergic neurons transplanted into the striatum.
|
|
| 4. |
|
|
| 5. |
- Klaric, Lucija, et al.
(författare)
-
Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
-
Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
|
|
| 6. |
- Lindholm, Beata, et al.
(författare)
-
Future falls and/or near falls in people with Parkinson's disease : sensitivity and specificity of two retropulsion tests
- 2013
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Objective: To investigate the sensitivity and specificity of two retropulsion tests for identifying individuals with Parkinson’s disease that will fall and/or experiencing near falls. Background: People with PD have an increased risk for falls and experiencing near falls. They are particularly unstable backwards, and different retropulsion tests exist. Item 30 of the Unified Parkinson’s Disease Rating Scale (UPDRS) is most common, involving an expected shoulder pull. Others advocate using an unexpected shoulder pull, e.g. the Nutt Retropulsion test (NRT). Methods: The study included 104 people with PD (mean age and PD-duration, 68 and 4.7 years, respectively) visiting a neurological clinic during 2006–2011. Those >80 years of age, requiring support in standing or did not understand the instructions were excluded. UPDRS and NRT assessments were conducted in the “on” condition. Participants then registered all falls and near falls by using a diary for six months. Based on this, participants were defined as “stable” (no falls/near falls) or “unstable” (1 fall / near fall). Sensitivity, specificity, positive and negative predictive values were calculated. Results: Mean (SD) score for UPDRS III was 14.5 (8.1). Fiftyfive (53%) participants were classified as “stable” and 49 (47%) as “unstable”. Both the NRT and item 30 (UPDRS) scores differed significantly (p = 0.003) between the groups. Mean NRT and item 30 scores were 0.18 (0.51) and 0.33 (0.61) for the “stable” group versus 0.63 (0.88) and 0.71 (0.74) for the “unstable” group. Sensitivity/specificity were 37%/87% (NRT), and 55%/75% (UPDRS item 30). Positive/negative predictive values were 72%/61% (NRT) and 66%/65% (UPDRS item 30). Conclusions: In this mildly affected sample, both NRT and item 30 had low sensitivity in detecting prospective falls and/or near falls over six months. Our findings speak against using either of these tests alone for this purpose and support previous recommendations of using multiple tests when targeting balance problems in people withPD.
|
|
| 7. |
- Lindholm, Beata, et al.
(författare)
-
Prediction of falls and/or near falls by using tandem gait performance in people with mild Parkinson’s disease
- 2015
-
Ingår i: [Host publication title missing]. ; 30, s. 100-100
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Objective: To investigate whether tandem gait test (TG) can predict future falls and/or near falls in people with Parkinson’s disease (PD). Background: People with PD have balance problems and an increased risk for falls. Although TG has been considered a predictor of falls, no PD-study has controlled results for demographic and disease-specific characteristics or included near falls when investigating falls prospectively. Methods: The study included 141 participants with PD (mean age and PD-duration, 68 and 4 years, respectively). Those >80 years of age, requiring support in standing or did not understand the instructions were excluded. TG includes taking 10 consecutive tandem steps along a straight line without walking aids and support, with eyes open. Performance was scored as follows: no side steps=0; one or more side steps=1; unable to take 4 consecutive steps=2. If TG was abnormal ("1 side steps) during the first attempt, a second trial was allowed and the best performance was registered. Anti-Parkinsonian medications were recorded from medical records. All assessments were conducted in the “on” condition. Participants thereafter registered all falls and near falls by using a diary for six months. Results: Mean score for UPDRS III was 14 (SD 8.0). The median (q1-q3) daily total levodopa equivalent (LDE) dose (mg) was 400 (286-600). Sixty-three participants (45%) experienced ≥1 fall and/or near fall. The median (q1-q3) TG score was 2 (1-2) for those that experienced falls and/or near falls and 0 (0-1) for those without any incidents. Logistic regression (controlling for age, gender, UPDRS III and daily LDE dose) showed that TG score 2 (OR, 5.40; 95% CI, 1.75-16.70; P=0.003) predicted falls and/or near falls. TG score 1 was not significant (OR, 2.24; 95% CI, 0.84-5.98; P=0.109). This model correctly classified 39/63 (62%) of individuals with falls and/or near falls and 64/78 (82%) of individuals without any incidence, and accounted for 32% of the variability between groups. Conclusions: The results suggest that TG may be able to predict a future fall and/or near fall in people with mild PD. Further studies using larger samples are needed for firmer conclusions and establishment of additional properties in relation to other assessments.
|
|
| 8. |
- Lindholm, Beata, et al.
(författare)
-
Prediction of instability in people with Parkinson's disease - clinical balance and gait tests
- 2013
-
Ingår i: [Publication information missing]. ; 28(S1), s. 163-163
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Objective: To explore whether clinical balance and gait tests can predict instability (falls and/or near falls) in people with Parkinson’s disease (PD). Background: Current PD-studies suggest that multiple balance tests should be used in order to predict falls. However, few studies have included near falls when investigating falls prospectively as recommended. Methods: The study included 74 people with PD (mean age and PD-duration, 69 and 4.9 years, respectively) visiting a neurological clinic during 2006–2010. Those >80 years of age, requiring support in standing or did not understand the instructions were excluded. Assessments included: the Berg Balance Scale (BBS, 0–56 points), Nutt Retropulsion test (NRT, dichotomized; 0 = "normal”, 1 = “abnormal”), tandem gait test (TG, dichotomized; 0 = “normal”, 1 = “abnormal”), 10-meter walk test (fast speed, m/s), and Timed Up & Go test (TUG, s). All assessments were conducted in the “on” condition. Participants then registered all falls and near falls by using a diary for six months. Results: Mean score for UPDRS III was 14 (SD 7.5). Thirty-six participants (49%) experienced 1 fall and/or near fall (“unstable” group), whereas 38 (51%) had no incidents at all (“stable” group). Simple logistic regression analyses (controlling for age and gender) showed that (P0.05 in all instances) the NRT was the strongest predictor (OR = 5.70) followed by TG (OR = 3.45). Better BBS-scores (OR = 0.88) and gait speed (OR = 0.26) were associated with a decreased risk of instability. The longer time to perform TUG, the higher risk of being unstable (OR = 1.14). When considering all five variables (i.e. tests) simultaneously only BBS was found significant (OR = 0.91, P 5 0.04). Conclusions: Clinical balance and gait tests can predict a future instability in people with PD. Further studies using larger samples are needed for firmer conclusions and to establish sensitivity/specificity and cut-off values for these tests.
|
|
| 9. |
- Lindholm, Beata, et al.
(författare)
-
Walking difficulties is the strongest contributing factor to fear of falling among people with mild Parkinson’s disease
- 2013
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Objective: Fear of falling is common among people with Parkinson’s disease (PD) and may cause activity limitations and restrictions in participation. The aim of this study was to investigate contributing factors to fall-related self-efficacy in a clinical sample of people with PD. Methods: The study included 104 people with PD that visited a neurological clinic during 2006-2011. Those >80 years of age, requiring support in standing or that did not understand the instructions were excluded. Mean (SD) age and PD-duration were 68 (9.4) and 5 (4.2) years, respectively; the mean (SD) “on” phase UPDRS III score was 14.5 (8.1). Fall-related self-efficacy (the dependent variable) was investigated with the Swedish version of the Falls Efficacy Scale, i.e. FES(S). Multiple linear regression analysis included independent variables targeting walking difficulties in daily life, freezing of gait, dyskinesia, fatigue, need of help in daily activities, age, PD-duration, history of falls/near falls, and pain. Results: The median FES(S) score was 117 (q1-q3, 70−129; minmax, 11−130). Three significant independent variables were identified explaining 66% of the variance in FES(S) scores. The strongest contributing factor to fall-related self-efficacy was walking difficulties (explaining 60%), followed by fatigue and need for help in daily activities. These observations suggest that walking difficulties in daily life is the strongest contributing factor to fall-related selfefficacy in a mildly affected PD-sample. Targeting walking difficulties may help reduce fear of falling among people with PD.
|
|
| 10. |
- Macdonald-Dunlop, Erin, et al.
(författare)
-
Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases
- 2021
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis-instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohn’s Disease as well as 2 novel therapeutic targets: IL-27 (Crohn’s disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology.
|
|
