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Parkinson's disease is a type of amyloidosis featuring accumulation of amyloid fibrils of ?-synuclein.

ABSTRACT: Many neurodegenerative diseases are characterized by the accumulation of abnormal protein aggregates in the brain. In Parkinson's disease (PD), ?-synuclein (?-syn) forms such aggregates called Lewy bodies (LBs). Recently, it has been reported that aggregates of ?-syn with a cross-? structure are capable of propagating within the brain in a prionlike manner. However, the presence of cross-? sheet-rich aggregates in LBs has not been experimentally demonstrated so far. Here, we examined LBs in thin sections of autopsy brains of patients with PD using microbeam X-ray diffraction (XRD) and found that some of them gave a diffraction pattern typical of a cross-? structure. This result confirms that LBs in the brain of PD patients contain amyloid fibrils with a cross-? structure and supports the validity of in vitro propagation experiments using artificially formed amyloid fibrils of ?-syn. Notably, our finding supports the concept that PD is a type of amyloidosis, a disease featuring the accumulation of amyloid fibrils of ?-syn.

SUBMITTER: Araki K

PROVIDER: S-EPMC6731630 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Parkinson's disease is a type of amyloidosis featuring accumulation of amyloid fibrils of α-synuclein.

Araki Katsuya K Yagi Naoto N Aoyama Koki K Choong Chi-Jing CJ Hayakawa Hideki H Fujimura Harutoshi H Nagai Yoshitaka Y Goto Yuji Y Mochizuki Hideki H

Proceedings of the National Academy of Sciences of the United States of America 20190819 36

Many neurodegenerative diseases are characterized by the accumulation of abnormal protein aggregates in the brain. In Parkinson's disease (PD), α-synuclein (α-syn) forms such aggregates called Lewy bodies (LBs). Recently, it has been reported that aggregates of α-syn with a cross-β structure are capable of propagating within the brain in a prionlike manner. However, the presence of cross-β sheet-rich aggregates in LBs has not been experimentally demonstrated so far. Here, we examined LBs in thin ...[more]

PMID: 31427526

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Project description: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. ?-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 ?-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 ?-synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society.

Dataset Information

Parkinson's disease is a type of amyloidosis featuring accumulation of amyloid fibrils of ?-synuclein.

Publications

Parkinson's disease is a type of amyloidosis featuring accumulation of amyloid fibrils of α-synuclein.

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