Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

Ysselstein, Daniel; Liu, Zhandong; Krainc, Dimitri

doi:10.1002/mds.27631

Cited by 39 publications

(43 citation statements)

References 126 publications

(249 reference statements)

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“…The link between PD and lysosomal pathways has already been established by both genetic and functional studies (Gan-Or et al 2015b;Robak et al 2017;Ysselstein et al 2019).…”

Section: Discussionmentioning

confidence: 99%

Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

Blauwendraat

Reed

Krohn

et al. 2019

Preprint

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Parkinson's disease (PD) is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of PD, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes.Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as PD and Lewy body dementia (LBD). These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4-to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known PD risk variants.Using multiple, large case-control datasets, totalling 217,165 individuals (22,757 PD cases, 13,431 PD proxy cases, 622 LBD cases and 180,355 controls), we identified 1,772 PD cases, 711 proxy cases and 7,624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent PD-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall PD genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S neurons were shown to have decreased Cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated PD risk and age at onset and demonstrate that variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have important implications for selection of GBA carriers for therapeutic interventions. 5

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“…The link between PD and lysosomal pathways has already been established by both genetic and functional studies (Gan-Or et al 2015b;Robak et al 2017;Ysselstein et al 2019).…”

Section: Discussionmentioning

confidence: 99%

Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

Blauwendraat

Reed

Krohn

et al. 2019

Preprint

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“…[86][87][88] Our discovery of a GBA deletion allele, expected to cause glucocerobrosidase haploinsufficiency, adds to other emerging evidence supporting a loss-offunction mechanism in GBA-associated PD. 89,90 It will be informative to screen for additional GBA CNVs in additional case/control cohorts-perhaps using ddPCR-to determine how commonly these alleles are associated with PD risk and estimate their effect size and penetrance.…”

Section: Discussionmentioning

confidence: 99%

Integrated Sequencing & Array Comparative Genomic Hybridization in Familial Parkinson’s Disease

Robak

Du²,

Yuan³

et al. 2019

Preprint

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Background: Parkinson's disease (PD) is a genetically heterogeneous condition; both single nucleotide variants (SNVs) and copy number variants (CNVs) are important genetic risk factors.We examined the utility of combining exome sequencing and genome-wide array-based comparative genomic hybridization (aCGH) for identification of PD genetic risk factors. Methods:We performed exome sequencing on 110 subjects with PD and a positive family history; 99 subjects were also evaluated using genome-wide aCGH. We interrogated exome sequencing and array comparative genomic hybridization data for pathogenic SNVs and CNVs at Mendelian PD gene loci. SNVs were confirmed via Sanger sequencing. CNVs were confirmed with custom-designed high-density aCGH, droplet digital PCR, and breakpoint sequencing. Results:Using exome sequencing, we discovered individuals with known pathogenic single nucleotide variants in GBA (p.E365K, p.T408M, p.N409S, p.L483P) and LRRK2 (p.R1441G and p.G2019S). Two subjects were each double heterozygotes for variants in GBA and LRRK2.Based on aCGH, we additionally discovered cases with an SNCA duplication and heterozygous intragenic GBA deletion. Five additional subjects harbored both SNVs (p.N52fs, p.T240M, p.P437L, p.W453*) and likely disrupting CNVs at the PARK2 locus, consistent with compound heterozygosity. In nearly all cases, breakpoint sequencing revealed microhomology, a mutational signature consistent with CNV formation due to DNA replication errors. Conclusions:Integrated exome sequencing and aCGH yielded a genetic diagnosis in 19.3% of our familial PD cohort. Our analyses highlight potential mechanisms for SNCA and PARK2 CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles.

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“…Emerging studies are showing that multiple variants in lysosomal storage disorder genes can contribute to PD susceptibility. 51,52 Deficiency of the lysosomal hydrolase glucocerebrosidase, encoded by GBA, leads to the most common lysosomal storage disorder, Gaucher disease. Generally, around 5%-15% of PD patients are reported to carry heterozygous GBA mutations.…”

Section: Autophagy-lysosomal Pathwaymentioning

confidence: 99%

Progress in the molecular pathogenesis and nucleic acid therapeutics for Parkinson's disease in the precision medicine era

Mastaglia

Fletcher

et al. 2020

Medicinal Research Reviews

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Parkinson's disease (PD) is one of the most common neurodegenerative disorders that manifest various motor and nonmotor symptoms. Although currently available therapies can alleviate some of the symptoms, the disease continues to progress, leading eventually to severe motor and cognitive decline and reduced life expectancy. The past two decades have witnessed rapid progress in our understanding of the molecular and genetic pathogenesis of the disease, paving the way for the development of new therapeutic approaches to arrest or delay the neurodegenerative process. As a result of these advances, biomarker-driven subtyping is making it possible to stratify PD patients into more homogeneous subgroups that may better respond to potential genetic-molecular pathway targeted disease-modifying therapies. Therapeutic nucleic acid oligomers can bind to target gene sequences with very high specificity in a base-pairing manner and precisely modulate downstream molecular events. Recently, nucleic acid therapeutics have proven effective in the treatment of a number of severe neurological and neuromuscular disorders, drawing increasing attention to the possibility of developing novel molecular therapies for PD. In this

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Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

Cited by 39 publications

References 126 publications

Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

Integrated Sequencing & Array Comparative Genomic Hybridization in Familial Parkinson’s Disease

Progress in the molecular pathogenesis and nucleic acid therapeutics for Parkinson's disease in the precision medicine era

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