Gene-Wise Association of Variants in Four Lysosomal Storage Disorder Genes in Neuropathologically Confirmed Lewy Body Disease

Clark, Lorraine N.; Chan, Robin B.; Cheng, Rong; Liu, Xinmin; Park, Naeun; Parmalee, Nancy L.; Kisselev, Sergey; Cortés, Etty; Torres, Patrícia; Pastores, Gregory M.; Vonsattel, Jean Paul; Alcalay, Roy N.; Marder, Karen; Honig, Lawrence S.; Fahn, Stanley; Mayeux, Richard; Shelanski, Michael L.; Paolo, Gilbert Di; Lee, Joseph H.

doi:10.1371/journal.pone.0125204

Cited by 56 publications

(62 citation statements)

References 35 publications

(34 reference statements)

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“…Thus far, not including the current study, SMPD1 variants have been associated with PD or synucleinopathy risk in 7 independent cohorts: 2 of Ashkenazi Jewish origin, 2 Chinese, 2 European, and 1 North American . In these studies, as well as in our cohort, only some of the mutations were associated with PD, whereas other SMPD1 mutations, including some that can cause Niemann‐Pick type A/B, were not associated with PD.…”

Section: Discussionmentioning

confidence: 39%

“…Variants in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), are among the most common risk factors for PD, found in 3%‐20% of PD patients from different populations . Recently, mutations in another lysosomal gene involved in sphingolipid metabolism, SMPD1 , which encodes the lysosomal enzyme acid sphingomyelinase (ASMase), have also been associated with an increased risk for PD . In the Ashkenazi Jewish population, specific Niemann‐Pick type A (NPA)‐causing SMPD1 mutations, p.L302P (also called p.L304P) and p.fsP330 (also called p.F333Sfs*52 or c.996delC), were associated with PD in 2 independent studies .…”

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confidence: 99%

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SMPD1 mutations, activity, and α‐synuclein accumulation in Parkinson's disease

et al. 2019

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Background SMPD1 (acid‐sphingomyelinase) variants have been associated with Parkinson's disease in recent studies. The objective of this study was to further investigate the role of SMPD1 mutations in PD. Methods SMPD1 was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid‐sphingomyelinase activity was measured by a mass spectrometry‐based assay in the New York cohort. α‐Synuclein levels were measured in vitro following CRISPR/Cas9‐mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)‐M17 cells. Lysosomal localization of acid‐sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid‐sphingomyelinase structure was performed. Results SMPD1 mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6‐8.2; P = 0.0025). In the Montreal/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%; P = 0.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid‐sphingomyelinase activity was associated with a 3.5‐ to 5.8‐year earlier onset of PD in the lowest quartile versus the highest quartile of acid‐sphingomyelinase activity (P = 0.01‐0.001). We further demonstrated that SMPD1 knockout and knockdown resulted in increased α‐synuclein levels in HeLa and BE(2)‐M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid‐sphingomyelinase to the lysosome. Conclusions Our results support an association between SMPD1 variants, acid‐sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid‐sphingomyelinase activity may lead to α‐synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society

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Section: Discussionmentioning

confidence: 39%

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SMPD1 mutations, activity, and α‐synuclein accumulation in Parkinson's disease

et al. 2019

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“…SMPD1 encodes the lysosomal enzyme aSMase, which converts sphingomyelin into ceramide. Different variants of SMPD1 were reported to increase the risk of developing PD in three independent Ashkenazi Jewish cohorts, one Chinese cohort, and in one mixed population . An association was found between the rs2071046 mutation in the gene‐encoding α‐N‐acetylglucosaminidase, which causes Sanfilippo A, with the risk for PD, together with the presence of α‐synuclein aggregates in the cortical brain tissue of patients with Sanfilippo A .…”

Section: Lsds and The Emerging Role Of Lysosomal Dysfunction In Pdmentioning

confidence: 95%

Lysosomal Dysfunction and α‐Synuclein Aggregation in Parkinson's Disease: Diagnostic Links

et al. 2016

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Lysosomal impairment is increasingly recognized as a central event in the pathophysiology of PD. Genetic associations between lysosomal storage disorders, including Gaucher disease and PD, highlight common risk factors and pathological mechanisms. Because the autophagy-lysosomal system is involved in the intralysosomal hydrolysis of dysfunctional proteins, lysosomal impairment may contribute to α-synuclein aggregation in PD. The degradation of α-synuclein is a complex process involving different proteolytic mechanisms depending on protein burden, folding, posttranslational modifications, and yet unknown factors. In this review, evidence for lysosomal dysfunction in PD and its intimate relationship with α-synuclein aggregation are discussed, after which the question of whether lysosomal proteins may serve as diagnostic biomarkers for PD is addressed. Changes in lysosomal enzymes, such as reduced glucocerebrosidase and cathepsin levels, have been observed in affected brain regions in PD patients. The detection of lysosomal proteins in CSF may provide a read-out of lysosomal dysfunction in PD and holds promise for the development of diagnostic PD biomarkers. Initial PD biomarker studies demonstrated altered lysosomal enzyme activities in CSF of PD patients when compared with controls. However, CSF lysosomal enzyme activities alone could not discriminate between PD patients and controls. The combination of CSF lysosomal markers with α-synuclein species and indicators of mitochondrial dysfunction, inflammation, and other pathological proteins in PD may be able to facilitate a more accurate diagnosis of PD. Further CSF biomarker studies are needed to investigate the utility of CSF lysosomal proteins as measures of disease state and disease progression in PD. © 2016 International Parkinson and Movement Disorder Society.

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“…As a support for this link between Cer and PD, the inhibition of acid ceramidase (encoded by ASAH1 ) by carmofur resulted in increased Cer levels in GCase‐deficient cells as well as reduced α‐syn levels in GBA1‐PD–derived dopaminergic neurons . It is also worthy to note that variants of acid sphingomyelinase (aSMase; encoded by SMPD1 ) and galactosylceramidase (GALC) are recognized as susceptibility factors for PD and other synucleinopathies. Together with GCase, these two enzymes catalyze the production of Cer within the lysosome.…”

Section: The Issue Of Alp Alterations In Sporadic Pdmentioning

confidence: 98%

The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

et al. 2019

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The accumulation and misfolding of α‐synuclein (α‐syn) represent the main pathological hallmark of PD. Overexpression of α‐syn and failure of cellular protein degradation systems play a major role in α‐syn aggregation. The discovery of PD‐associated genes related to the autophagic‐lysosomal pathway, such as VPS35, LRRK2, GBA1, SMPD1, GALC, ASAH1, SCARB2, CTSD, CTSB, and GLA, confirms the involvement of cellular clearance systems dysfunction in PD pathogenesis. Of importance, lysosomal enzyme activity is altered both in genetic and sporadic PD. Decreased lysosomal enzymes activities were measured in the same brain regions where α‐syn accumulates, suggesting that a crosstalk between α‐syn aggregation and autophagic‐lysosomal impairment may exist. The understanding of autophagic‐lysosomal pathway dysfunctions’ role in the pathogenesis and progression of synucleinopathies opened new perspectives for novel possible therapeutic strategies. In this article, the evidences and mechanisms of the reciprocal relation between autophagic‐lysosomal pathway impairment and misfolded α‐syn aggregation and propagation are reviewed, together with the most promising compounds targeting autophagic‐lysosomal pathway restoration as a disease‐modifying strategy for PD treatment. © 2019 International Parkinson and Movement Disorder Society

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Gene-Wise Association of Variants in Four Lysosomal Storage Disorder Genes in Neuropathologically Confirmed Lewy Body Disease

Cited by 56 publications

References 35 publications

SMPD1 mutations, activity, and α‐synuclein accumulation in Parkinson's disease

SMPD1 mutations, activity, and α‐synuclein accumulation in Parkinson's disease

Lysosomal Dysfunction and α‐Synuclein Aggregation in Parkinson's Disease: Diagnostic Links

The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

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