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- Labbé, Catherine, et al.
(författare)
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Role for the microtubule-associated protein tau variant p.A152T in risk of α-synucleinopathies.
- 2015
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Ingår i: Neurology. - 1526-632X. ; 85:19, s. 1680-1686
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Tidskriftsartikel (refereegranskat)abstract
- Objective:To assess the importance of MAPT variant p.A152T in the risk of synucleinopathies. Methods:In this case-control study, we screened a large global series of patients and controls, and assessed associations between p.A152T and disease risk. We included 3,229 patients with clinical Parkinson disease (PD), 442 with clinical dementia with Lewy bodies (DLB), 181 with multiple system atrophy (MSA), 832 with pathologically confirmed Lewy body disease (LBD), and 2,456 healthy controls. Results:The minor allele frequencies (MAF) in clinical PD cases (0.28%) and in controls (0.2%) were not found to be significantly different (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.63-2.98, p = 0.42). However, a significant association was observed with clinical DLB (MAF 0.68%, OR 5.76, 95% CI 1.62-20.51, p = 0.007) and LBD (MAF 0.42%, OR 3.55, 95% CI 1.04-12.17, p = 0.04). Additionally, p.A152T was more common in patients with MSA compared to controls (MAF 0.55%, OR 4.68, 95% CI 0.85-25.72, p = 0.08) but this was not statistically significant and therefore should be interpreted with caution. Conclusions:Overall, our findings suggest that MAPT p.A152T is a rare low penetrance variant likely associated with DLB that may be influenced by coexisting LBD and AD pathology. Given the rare nature of the variant, further studies with greater sample size are warranted and will help to fully explain the role of p.A152T in the pathogenesis of the synucleinopathies
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| 2. |
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| 3. |
- Puschmann, Andreas, et al.
(författare)
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Clinically meaningful parameters of progression and long-term outcome of Parkinson disease: An international consensus statement.
- 2015
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Ingår i: Parkinsonism & Related Disorders. - : Elsevier BV. - 1873-5126 .- 1353-8020. ; 21:7, s. 675-682
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson disease (PD) is associated with a clinical course of variable duration, severity, and a combination of motor and non-motor features. Recent PD research has focused primarily on etiology rather than clinical progression and long-term outcomes. For the PD patient, caregivers, and clinicians, information on expected clinical progression and long-term outcomes is of great importance. Today, it remains largely unknown what factors influence long-term clinical progression and outcomes in PD; recent data indicate that the factors that increase the risk to develop PD differ, at least partly, from those that accelerate clinical progression and lead to worse outcomes. Prospective studies will be required to identify factors that influence progression and outcome. We suggest that data for such studies is collected during routine office visits in order to guarantee high external validity of such research. We report here the results of a consensus meeting of international movement disorder experts from the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium, who convened to define which long-term outcomes are of interest to patients, caregivers and clinicians, and what is presently known about environmental or genetic factors influencing clinical progression or long-term outcomes in PD. We propose a panel of rating scales that collects a significant amount of phenotypic information, can be performed in the routine office visit and allows international standardization. Research into the progression and long-term outcomes of PD aims at providing individual prognostic information early, adapting treatment choices, and taking specific measures to provide care optimized to the individual patient's needs.
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| 4. |
- Puschmann, Andreas, et al.
(författare)
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Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism
- 2017
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 140:1, s. 98-117
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Tidskriftsartikel (refereegranskat)abstract
- SEE GANDHI AND PLUN-FAVREAU DOI101093/AWW320 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: It has been postulated that heterozygous mutations in recessive Parkinson's genes may increase the risk of developing the disease. In particular, the PTEN-induced putative kinase 1 (PINK1) p.G411S (c.1231G>A, rs45478900) mutation has been reported in families with dominant inheritance patterns of Parkinson's disease, suggesting that it might confer a sizeable disease risk when present on only one allele. We examined families with PINK1 p.G411S and conducted a genetic association study with 2560 patients with Parkinson's disease and 2145 control subjects. Heterozygous PINK1 p.G411S mutations markedly increased Parkinson's disease risk (odds ratio = 2.92, P = 0.032); significance remained when supplementing with results from previous studies on 4437 additional subjects (odds ratio = 2.89, P = 0.027). We analysed primary human skin fibroblasts and induced neurons from heterozygous PINK1 p.G411S carriers compared to PINK1 p.Q456X heterozygotes and PINK1 wild-type controls under endogenous conditions. While cells from PINK1 p.Q456X heterozygotes showed reduced levels of PINK1 protein and decreased initial kinase activity upon mitochondrial damage, stress-response was largely unaffected over time, as expected for a recessive loss-of-function mutation. By contrast, PINK1 p.G411S heterozygotes showed no decrease of PINK1 protein levels but a sustained, significant reduction in kinase activity. Molecular modelling and dynamics simulations as well as multiple functional assays revealed that the p.G411S mutation interferes with ubiquitin phosphorylation by wild-type PINK1 in a heterodimeric complex. This impairs the protective functions of the PINK1/parkin-mediated mitochondrial quality control. Based on genetic and clinical evaluation as well as functional and structural characterization, we established p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a partial dominant-negative function phenotype.
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| 6. |
- Watzlawik, Jens O., et al.
(författare)
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Basal activity of PINK1 and PRKN in cell models and rodent brain
- 2023
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Ingår i: Autophagy. - 1554-8627.
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Tidskriftsartikel (refereegranskat)abstract
- The ubiquitin kinase-ligase pair PINK1-PRKN recognizes and transiently labels damaged mitochondria with ubiquitin phosphorylated at Ser65 (p-S65-Ub) to mediate their selective degradation (mitophagy). Complete loss of PINK1 or PRKN function unequivocally leads to early-onset Parkinson disease, but it is debated whether impairments in mitophagy contribute to disease later in life. While the pathway has been extensively studied in cell culture upon acute and massive mitochondrial stress, basal levels of activation under endogenous conditions and especially in vivo in the brain remain undetermined. Using rodent samples, patient-derived cells, and isogenic neurons, we here identified age-dependent, brain region-, and cell type-specific effects and determined expression levels and extent of basal and maximal activation of PINK1 and PRKN. Our work highlights the importance of defining critical risk and therapeutically relevant levels of PINK1-PRKN signaling which will further improve diagnosis and prognosis and will lead to better stratification of patients for future clinical trials.
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