GBA1 deficiency negatively affects physiological α-synuclein tetramers and related multimers

被引：148

作者：

Kim, Sangjune ^{[1
,2
,3
]}

Yun, Seung Pil ^{[1
,2
,3
,4
]}

Lee, Saebom ^{[1
,2
,3
]}

Umanah, George Essien ^{[1
,2
,3
]}

Bandaru, Veera Venkata Ratnam ^{[1
,2
,3
]}

Yin, Xiling ^{[1
,2
,3
,4
]}

Rhee, Peter ^{[1
,2
,3
]}

Karuppagounder, Senthilkumar S. ^{[1
,2
,3
]}

Kwon, Seung-Hwan ^{[1
,2
]}

Lee, Hojae ^{[1
,2
,3
]}

Mao, Xiaobo ^{[1
,2
,3
,4
]}

Kim, Donghoon ^{[1
,2
,3
]}

Pandey, Akhilesh ^{[5
,6
]}

Lee, Gabsang ^{[1
,2
,3
,7
]}

Dawson, Valina L. ^{[1
,2
,3
,4
,7
,8
]}

Dawson, Ted M. ^{[1
,2
,3
,4
,7
,9
]}

Ko, Han Seok ^{[1
,2
,3
,4
,10
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Neuroregenerat Program, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Stem Cell Program, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA

[4] Adrienne Helis Malvin Med Res Fdn, New Orleans, LA 70130 USA

[5] Johns Hopkins Univ, Sch Med, Mckusick Nathans Inst Genet Med, Baltimore, MD 21205 USA

[6] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA

[7] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA

[8] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA

[9] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA

[10] Diana Helis Henry Med Res Fdn, New Orleans, LA 70130 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2018年 / 115卷 / 04期

关键词：

GBA1; alpha-synuclein; tetramers; glucosylceramide; Parkinson's disease; CHAPERONE-MEDIATED AUTOPHAGY; MOUSE MODEL; GLUCOCEREBROSIDASE MUTATIONS; PARKINSONS-DISEASE; CRYSTAL-STRUCTURE; DOPAMINE NEURONS; BINDING; CELLS; MULTICENTER; DEGRADATION;

D O I：

10.1073/pnas.1700465115

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Accumulating evidence suggests that alpha-synuclein (alpha-syn) occurs physiologically as a helically folded tetramer that resists aggregation. However, the mechanisms underlying the regulation of formation of alpha-syn tetramers are still mostly unknown. Cellular membrane lipids are thought to play an important role in the regulation of alpha-syn tetramer formation. Since glucocerebrosidase 1 (GBA1) deficiency contributes to the aggregation of alpha-syn and leads to changes in neuronal glycosphingolipids (GSLs) including gangliosides, we hypothesized that GBA1 deficiency may affect the formation of alpha-syn tetramers. Here, we show that accumulation of GSLs due to GBA1 deficiency decreases alpha-syn tetramers and related multimers and increases alpha-syn monomers in CRISPR-GBA1 knockout (KO) SH-SY5Y cells. Moreover, alpha-syn tetramers and related multimers are decreased in N370S GBA1 Parkinson's disease (PD) induced pluripotent stem cell (iPSC)-derived human dopaminergic (hDA) neurons and murine neurons carrying the heterozygous L444P GBA1 mutation. Treatment with miglustat to reduce GSL accumulation and overexpression of GBA1 to augment GBA1 activity reverse the destabilization of alpha-syn tetramers and protect against alpha-syn preformed fibril-induced toxicity in hDA neurons. Taken together, these studies provide mechanistic insights into how GBA1 regulates the transition from monomeric alpha-syn to alpha-syn tetramers and multimers and suggest unique therapeutic opportunities for PD and dementia with Lewy bodies.

引用

页码：798 / 803

页数：6

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