| 1. |
- Berge-Seidl, Victoria, et al.
(författare)
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The GBA variant E326K is associated with Parkinson's disease and explains a genome-wide association signal
- 2017
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Ingår i: Neuroscience Letters. - : Elsevier. - 0304-3940 .- 1872-7972. ; 658, s. 48-52
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Coding variants in the GBA gene have been identified as the numerically most important genetic risk factors for Parkinson's disease (PD). In addition, genome-wide association studies (GWAS) have identified associations with PD in the SYT11-GBA region on chromosome 1q22, but the relationship to GBA coding variants have remained unclear. The aim of this study was to sequence the complete GBA gene in a clinical cohort and to investigate whether coding variants within the GBA gene may be driving reported association signals. Methods: We analyzed high-throughput sequencing data of all coding exons of GBA in 366 patients with PD. The identified low-frequency coding variants were genotyped in three Scandinavian case-controls series (786 patients and 713 controls). Previously reported risk variants from two independent association signals within the SYT11-GBA locus on chromosome 1 were also genotyped in the same samples. We performed association analyses and evaluated linkage disequilibrium (LD) between the variants. Results: We identified six rare mutations (1.6%) and two low-frequency coding variants in GBA. E326K (rs2230288) was significantly more frequent in PD patients compared to controls (OR 1.65, p = 0.03). There was no clear association of T369M (rs75548401) with disease (OR 1.43, p = 0.24). Genotyping the two GWAS hits rs35749011 and rs114138760 in the same sample set, we replicated the association between rs35749011 and disease status (OR 1.67, p = 0.03), while rs114138760 was found to have similar allele frequencies in patients and controls. Analyses revealed that E326K and rs35749011 are in very high LD (r(2) 0.95). Conclusions: Our results confirm that the GBA variant E326K is a susceptibility allele for PD. The results suggest that E326K may fully account for the primary association signal observed at chromosome 1q22 in previous GWAS of PD.
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| 2. |
- Lunde, Kristin Aaser, et al.
(författare)
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Association of glucocerebrosidase polymorphisms and mutations with dementia in incident Parkinson's disease
- 2018
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Ingår i: Alzheimer's & Dementia. - : Elsevier. - 1552-5260 .- 1552-5279. ; 14:10, s. 1293-1301
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionBoth polymorphisms and mutations in glucocerebrosidase (GBA) may influence the development of dementia in patients with Parkinson's disease.MethodsFour hundred forty-two patients and 419 controls were followed for 7 years. Dementia was diagnosed using established criteria. Participants were analyzed for GBA genetic variants, including E326K, T369M, and L444P. Associations between GBA carrier status and dementia were assessed with Cox survival analysis.ResultsA total of 12.0% of patients with Parkinson's disease carried a GBA variant, and nearly half (22/53) of them progressed to dementia during follow-up. Carriers of deleterious GBA mutations (adjusted hazard ratio 3.81, 95% confidence interval 1.35 to 10.72; P = .011) or polymorphisms (adjusted hazard ratio 1.79; 95% confidence interval 1.07 to 3.00; P = .028) progressed to dementia more rapidly than noncarriers.DiscussionGBA variants are of great clinical relevance for the development of dementia in Parkinson's disease, especially due to the relatively higher frequency of these alleles compared with other risk alleles.
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| 3. |
- Alves, Guido, et al.
(författare)
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Cerebrospinal fluid amyloid-β and phenotypic heterogeneity in de novo Parkinson's disease.
- 2013
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Ingår i: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 84:5, s. 537-43
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Tidskriftsartikel (refereegranskat)abstract
- In Parkinson's disease (PD), the motor presentation characterised by postural instability/gait difficulties (PIGD) heralds accelerated motor, functional and cognitive decline, as compared with the more benign tremor-dominant (TD) variant. This makes the PIGD complex an attractive target for the discovery of prognostic biomarkers in PD.
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| 4. |
- Alves, Guido, et al.
(författare)
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CSF amyloid-β and tau proteins, and cognitive performance, in early and untreated Parkinson's Disease: the Norwegian ParkWest study
- 2010
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Ingår i: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 81:10, s. 1080-1086
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Tidskriftsartikel (refereegranskat)abstract
- Background Alzheimer's disease (AD) pathology is found in a considerable portion of patients with Parkinson's disease (PD), particularly those with early dementia (PDD). Altered cerebrospinal fluid (CSF) levels of amyloid-beta (Abeta) and tau proteins have been found in PDD, with intermediate changes for Abeta42 in non-demented PD. The authors investigated whether AD-related CSF protein levels are altered and relate to neuropsychological performance in early, untreated PD. Methods CSF concentrations of Abeta42, Abeta40 and Abeta38 were measured by electrochemiluminiscene and levels of total tau (T-tau) and phosphorylated tau (P-tau) by ELISA in 109 newly diagnosed, unmedicated, non-demented, community-based PD patients who had undergone comprehensive neuropsychological testing, and were compared with those of 36 age-matched normal controls and 20 subjects with mild AD. Results PD patients displayed significant reductions in Abeta42 (19%; p=0.009), Abeta40 (15.5%; p=0.008) and Abeta38 (23%; p=0.004) but not T-tau (p=0.816) or P-tau (p=0.531) compared with controls. CSF Abeta42 reductions in PD were less marked than in AD (53%; p=0.002). Sequential regression analyses demonstrated significant associations between CSF levels of Abeta42 (beta=0.205; p=0.019), Abeta40 (beta=0.378; p<0.001) and Abeta38 (beta=0.288; p=0.001) and memory impairment, but not executive-attentional or visuospatial dysfunction. Tau protein levels did not correlate with cognitive measures. Conclusion CSF Abeta levels are altered in a subset of patients with early PD and relate to memory impairment. Our study suggests that alterations in Abeta protein metabolism may contribute to the heterogeneity in pattern and course of cognitive decline associated with PD. Longitudinal studies are needed to clarify the clinical significance of CSF Abeta peptides as prognostic biomarkers in PD.
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| 5. |
- Björkblom, Benny, et al.
(författare)
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Parkinson Disease Protein DJ-1 Binds Metals and Protects against Metal-induced Cytotoxicity
- 2013
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Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 288:31, s. 22809-22820
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Tidskriftsartikel (refereegranskat)abstract
- The progressive loss of motor control due to reduction of dopamine-producing neurons in the substantia nigra pars compacta and decreased striatal dopamine levels are the classically described features of Parkinson disease (PD). Neuronal damage also progresses to other regions of the brain, and additional non-motor dysfunctions are common. Accumulation of environmental toxins, such as pesticides and metals, are suggested risk factors for the development of typical late onset PD, although genetic factors seem to be substantial in early onset cases. Mutations of DJ-1 are known to cause a form of recessive early onset Parkinson disease, highlighting an important functional role for DJ-1 in early disease prevention. This study identifies human DJ-1 as a metal-binding protein able to evidently bind copper as well as toxic mercury ions in vitro. The study further characterizes the cytoprotective function of DJ-1 and PD-mutated variants of DJ-1 with respect to induced metal cytotoxicity. The results show that expression of DJ-1 enhances the cells' protective mechanisms against induced metal toxicity and that this protection is lost for DJ-1 PD mutations A104T and D149A. The study also shows that oxidation site-mutated DJ-1 C106A retains its ability to protect cells. We also show that concomitant addition of dopamine exposure sensitizes cells to metal-induced cytotoxicity. We also confirm that redox-active dopamine adducts enhance metal-catalyzed oxidation of intracellular proteins in vivo by use of live cell imaging of redox-sensitive S3roGFP. The study indicates that even a small genetic alteration can sensitize cells to metal-induced cell death, a finding that may revive the interest in exogenous factors in the etiology of PD.
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| 6. |
- Björkblom, Benny, et al.
(författare)
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Reactive oxygen species-mediated DJ-1 monomerization modulates intracellular trafficking involving karyopherin beta 2
- 2014
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Ingår i: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 34:16, s. 3024-3040
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in DJ-1 are a cause of recessive, early-onset Parkinson's disease (PD). Although oxidative stress and mitochondrial integrity have been implicated in PD, it is largely unknown why neurons degenerate. DJ-1 is involved in oxidative stress-mediated responses and in mitochondrial maintenance; however, its specific function remains vague. Here we show that DJ-1 exhibits neuronal dynamic intracellular trafficking, with dimeric/monomeric cycling modulated by the oxidative environment. We demonstrate that oxidative stress enhances monomerization of wild-type cytosolic DJ-1, leading to nuclear recruitment. The pathogenic DJ-1/E163K variant is unable to homodimerize but is retained in the cytosol upon wild-type DJ-1 heterodimerization. We found that this wild-type/pathogenic heterodimer is disrupted by oxidative stress, leading to DJ-1/E163K mitochondrial translocation. We further demonstrated that endogenously expressed wild-type DJ-1 is imported into neuronal nuclei as a monomer and that nucleo-cytoplasmic transport is oxidative stress mediated. We identified a novel proline-tyrosine nuclear localization signal (PY-NLS) in DJ-1, and we found that nuclear monomeric DJ-1 import is mediated by an oxidative stress-dependent interaction with karyopherin beta 2. Our study provides evidence that oxidative stress-mediated intracellular trafficking of DJ-1, mediated by dynamic DJ-1 dimeric/monomeric cycling, is implicated in PD pathogenesis.
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| 7. |
- Fall, Per-Arne, 1943-
(författare)
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Aspects of Parkinson's disease. Epidemiology, risk factors and ECT in advanced disease
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The purpose was to investigate some aspects of epidemiology, risk factors and treatment with ECT in advanced Parkinson’s disease (PD).In study I, we performed a descriptive epidemiologic population-based survey in the Central Health Care District in Östergötland in south-east Sweden, with a population of almost 150,000 inhabitants 1989. The case finding was accomplished in three ways: 1. Collection of all prescriptions for Parkinson’s disease. 2. Search in medical files. 3. Checking with all nursing homes in the area. The crude prevalence was found to be 115 per 100,000 inhabitants. When we used the European Standard Population as a tool for easy comparisons of PD prevalence between different areas and time periods 76 PD-cases per 100,000 inhabitants were found. The corresponding incidences were 11.0 (crude) and 7.9 (age standardised) per 100,000 person-years. Mean age at onset was 65.6. A low prevalence and a high age at onset suggested that e.g. environmental factors could influence the occurrence of PD, and the results implies that only few such factors were present in the investigated area.The findings led to study II, a case-control study which investigated the possible impact of nutritional and environmental risk factors for idiopathic Parkinson’s disease (IP), including 113 cases and 263 control subjects. Dietary, drinking, and smoking habits, as well as previous occupation, were requested in a structured questionnaire. No increased risk was found for any of the nutrients. A reduced risk was found for coffee, wine, and spirits but also for broiled meat, smoked ham or meat, eggs, French loaf or white bread, and tomatoes. These findings could indicate an antioxidant effect. Frequency of preceding and present smoking was reduced in IP patients. Possible mechanisms are discussed. Various occupational groups and exposures were analysed and increased risks of IP in men were found for agricultural work, pesticide exposure, male carpenters, and in female cleaners.In advanced PD there is a need for further therapeutic improvements, and electroconvulsive therapy (ECT) is one insufficiently explored and evaluated method. In study III ECT 16 non-depressed, nondemented PD patients with advanced disease were treated with ECT. In all patients an antiparkinsonian effect of ECT was seen, lasting between a few days and 18 months. Five patients, all with signs of blood brain barrier damage, developed transitory mental confusion after ECT. The results indicated that ECT could cause increased dopaminergic activity, which led us to study IV. Single photon emission computed tomography (SPECT) with the cocaine analogue [123I]-β-CIT was used in order to visualise dopaminergic neurones in the brain. Six patients with PD were examined before and after a series of ECT, and in three cases SPECT was also repeated after one year. The side-to-side difference in the radiotracer uptake was found to be significantly lower in striatum located contralaterally to the part of the body with most pronounced symptomatology. No significant change in uptake of [123I]-β-CIT was seen after ECT, although all patients improved and the most pronounced improvement was seen in patients with less advanced PD.Study V points at two new positive observations with maintenance ECT (MECT). i.e. repeated ECT treatment of PD. One patient had either severe mental side effects on higher L-dopa doses or intolerable parkinsonian symptoms on lower doses. MECT implied marked improvement in parkinsonian symptoms without mental side effects. Another PD patient, who also had a mental depression, showed slight improvement of motor symptoms on a series of ECT. When treated with MECT further antiparkinsonian effects were seen.
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| 8. |
- Førland, Marthe Gurine, et al.
(författare)
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Validation of a new assay for α-synuclein detection in cerebrospinal fluid.
- 2017
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Ingår i: Clinical chemistry and laboratory medicine. - : Walter de Gruyter GmbH. - 1437-4331 .- 1434-6621. ; 55:2
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal α-synuclein aggregation and deposition is the pathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), but is also found in Alzheimer disease (AD). Therefore, there is a gaining interest in α-synuclein in cerebrospinal fluid (CSF) as potential biomarker for these neurodegenerative diseases. To broaden the available choices of α-synuclein measurement in CSF, we developed and validated a new assay for detecting total α-synuclein.
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| 9. |
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| 10. |
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