The genetic landscape of Parkinson's disease

Lunati, Ariane; Lesage, Suzanne; Brice, Alexis

doi:10.1016/j.neurol.2018.08.004

Cited by 169 publications

(173 citation statements)

References 176 publications

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“…Aside from the duplications of SNCA , other SNVs and small indel variants of the other known PD‐related genes were examined using the WGS data. A total of 44 genes ( ATP13A2 , ATP1A3 , ATXN2 , C19orf12 , CHCHD2 , CP , DNAJC6 , DNAJC13 , EIF4G1 , FA2H , FBXO7 , FTL , GBA , GCH1 , GLB1 , GIGYF2 , HTRA2 , LRRK2 , PANK2 , PARK7 , PINK1 , PLA2G6 , PODXL , POLG , PRKN , PTRHD1 , PTS , QDPR , RAB39B , RIC3 , SLC30A10 , SLC6A3 , SNCA , SPG11 , SPR , SYNJ1 , TAF1 , TH , TMEM230 , UCHL1 , VPS13C , VPS35 , WDR45 , and ZFYVE26 ) related to several conditions of parkinsonism were searched for additional pathogenic variants. No pathogenic variants were detected in the coding exons with 10 bp of intronic flanking regions, whereas case 4 carried an intron variant of unknown significance (VUS) in ATP13A2 (c.2529 + 9G > A) and case 6 carried a missense VUS in SPG11 (c.7006A > G).…”

Section: Resultsmentioning

confidence: 99%

Replication‐Based Rearrangements Are a Common Mechanism for SNCA Duplication in Parkinson's Disease

Seo

Bacolla

Yoo³

et al. 2020

Movement Disorders

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Background SNCA multiplication is a genomic cause of familial PD, showing dosage‐dependent toxicity. Until now, nonallelic homologous recombination was suggested as the mechanism of SNCA duplication, based on various types of repetitive elements found in the spanning region of the breakpoints. However, the sequence at the breakpoint was analyzed only for 1 case. Objectives We have analyzed the breakpoint sequences of 6 patients with PD who had duplicated SNCA using whole‐genome sequencing data to elucidate the mechanism of SNCA duplication. Methods Six patient samples with SNCA duplication underwent whole‐genome sequencing. The duplicated regions were defined with nucleotide‐resolution breakpoints, which were confirmed by junction polymerase chain reaction and Sanger sequencing. The search for potential non‐B DNA‐forming sequences and stem‐loop structure predictions was conducted. Results Duplicated regions ranged from the smallest region of 718.3 kb to the largest one of 4,162 kb. Repetitive elements were found at 8 of the 12 breakpoint sequences on each side of the junction, but none of the pairs shared overt homologies. Five of these six junctions had microhomologies (2–4 bp) at the breakpoint, and a short stretch of sequences was inserted in 3 cases. All except one junction were located within or next to stem‐loop structures. Conclusion Our study has determined that homologous recombination mechanisms involving repetitive elements are not the main cause of the duplication of SNCA. The presence of microhomology at the junctions and their position within stem‐loop structures suggest that replication‐based rearrangements may be a common mechanism for SNCA amplification. © 2020 International Parkinson and Movement Disorder Society

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Section: Resultsmentioning

confidence: 99%

Replication‐Based Rearrangements Are a Common Mechanism for SNCA Duplication in Parkinson's Disease

Seo

Bacolla

Yoo³

et al. 2020

Movement Disorders

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“…PD may have a number of different causes, and several pathogenic mechanisms have been proposed to contribute to the apoptotic death of neurons (6)(7)(8)(9)(10). In the majority of cases, the etiologies are unknown and probably complex.…”

Section: Introductionmentioning

confidence: 99%

Enhancing glycolysis attenuates Parkinson’s disease progression in models and clinical databases

Cai¹,

Zhang

Simmering³

et al. 2019

Journal of Clinical Investigation

194

199

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Parkinson's disease (PD) is a common neurodegenerative disease that lacks therapies to prevent progressive neurodegeneration. Impaired energy metabolism and reduced ATP levels are common features of PD. Previous studies revealed that terazosin (TZ) enhances the activity of phosphoglycerate kinase 1 (PGK1), thereby stimulating glycolysis and increasing cellular ATP levels. Therefore, we asked whether enhancement of PGK1 activity would change the course of PD. In toxin-induced and genetic PD models in mice, rats, flies, and induced pluripotent stem cells, TZ increased brain ATP levels and slowed or prevented neuron loss. The drug increased dopamine levels and partially restored motor function. Because TZ is prescribed clinically, we also interrogated 2 distinct human databases. We found slower disease progression, decreased PD-related complications, and a reduced frequency of PD diagnoses in individuals taking TZ and related drugs. These findings suggest that enhancing PGK1 activity and increasing glycolysis may slow neurodegeneration in PD.

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“…The age at onset is an essential indicator in the case of PD with such great etiological heterogeneity. For instance, despite a highly variable age at onset, patients with LRRK2 mutations tend to have later onset PD, whereas patients with VPS35 mutations are more likely to have an earlier onset . A significant association of the LRRK2 A419V variant was only found among early‐onset PD in the ethnic Han Chinese population, and not among late‐onset PD …”

Section: Discussionmentioning

confidence: 98%

“…With the advent of next‐generation sequencing, a growing number of causative genes with Mendelian inheritance have been identified in PD patients. However, several of these genes, particularly those associated with dominant inheritance ( DNAJC13 , TMEM230 , GIGYF2 , HTRA2 , RIC3 , EIF4G1 , UCHL1 , and CHCHD2 ), are still awaiting confirmation or have not been replicated, thus casting doubt on their pathogenicity . Recently, Quadri and colleagues identified LRP10 as a novel causative gene for autosomal‐dominant PD.…”

Section: Discussionmentioning

confidence: 99%

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LRP10 in autosomal‐dominant Parkinson's disease

et al. 2019

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Background Recently, the LRP10 gene has been identified as a novel genetic cause in individuals affected by Parkinson's disease (PD), Parkinson's disease dementia, or dementia with Lewy bodies. Objective We investigated the involvement of LRP10 mutations in Chinese patients with familial PD and reviewed previous studies of LRP10 mutations in patients with PD. Methods A mutation analysis of the LRP10 gene was performed in a cohort of 205 unrelated Chinese patients with familial PD. Burden analysis was conducted using data from the Genome Aggregation Database and 5 genetic studies of LRP10 in patients with PD (including our cohort). Results A total of 3 novel potentially pathogenic variants, c.32T>A (p.L11H), c.1184G>A (p.R395H), and c.1333G>A (p.A445T), were detected in 3 probands of our cohort. However, burden analysis argued against an overrepresentation of variant alleles in patients with PD. Conclusions Genetic screening of the LRP10 gene in our cohort may provide independent, albeit limited, evidence for the pathogenicity of LRP10 in familial PD. Burden analysis using data from current studies failed to support the association between LRP10 and PD in general. Thus, more robust replication studies are warranted to determine the involvement of LRP10 in the pathogenesis of PD. © 2019 International Parkinson and Movement Disorder Society

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The genetic landscape of Parkinson's disease

Cited by 169 publications

References 176 publications

Replication‐Based Rearrangements Are a Common Mechanism for SNCA Duplication in Parkinson's Disease

Replication‐Based Rearrangements Are a Common Mechanism for SNCA Duplication in Parkinson's Disease

Enhancing glycolysis attenuates Parkinson’s disease progression in models and clinical databases

LRP10 in autosomal‐dominant Parkinson's disease

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