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

Sangjune Kim, Seung Pil Yun, Saebom Lee, George Umanah, Veera Venkata Ratnam Bandaru, Xiling Yin, Peter Rhee, Senthilkumar Karuppagounder, Seung Hwan Kwon, Hojae Lee, Xiaobo Mao, Donghoon Kim, Akhilesh Pandey, Gabsang Lee, Valina Dawson, Ted M Dawson, Hanseok Seok Ko

Research output: Contribution to journalArticle

Abstract

Accumulating evidence suggests that α-synuclein (α-syn) occurs physiologically as a helically folded tetramer that resists aggregation. However, the mechanisms underlying the regulation of formation of α-syn tetramers are still mostly unknown. Cellular membrane lipids are thought to play an important role in the regulation of α-syn tetramer formation. Since glucocerebrosidase 1 (GBA1) deficiency contributes to the aggregation of α-syn and leads to changes in neuronal glycosphingolipids (GSLs) including gangliosides, we hypothesized that GBA1 deficiency may affect the formation of α-syn tetramers. Here, we show that accumulation of GSLs due to GBA1 deficiency decreases α-syn tetramers and related multimers and increases α-syn monomers in CRISPR-GBA1 knockout (KO) SH-SY5Y cells. Moreover, α-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 α-syn tetramers and protect against α-syn preformed fibril-induced toxicity in hDA neurons. Taken together, these studies provide mechanistic insights into how GBA1 regulates the transition from monomeric α-syn to α-syn tetramers and multimers and suggest unique therapeutic opportunities for PD and dementia with Lewy bodies.

Original languageEnglish (US)
Pages (from-to)798-803
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number4
DOIs
StatePublished - Jan 23 2018

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Synucleins
Glucosylceramidase
Gaucher Disease
Glycosphingolipids
Dopaminergic Neurons
Parkinson Disease
Clustered Regularly Interspaced Short Palindromic Repeats
Lewy Body Disease
Induced Pluripotent Stem Cells
Gangliosides
Membrane Lipids
Neurons
Mutation

Keywords

  • GBA1
  • Glucosylceramide
  • Parkinson’s disease
  • Tetramers
  • α-synuclein

ASJC Scopus subject areas

  • General

Cite this

GBA1 deficiency negatively affects physiological α-synuclein tetramers and related multimers. / Kim, Sangjune; Yun, Seung Pil; Lee, Saebom; Umanah, George; Bandaru, Veera Venkata Ratnam; Yin, Xiling; Rhee, Peter; Karuppagounder, Senthilkumar; Kwon, Seung Hwan; Lee, Hojae; Mao, Xiaobo; Kim, Donghoon; Pandey, Akhilesh; Lee, Gabsang; Dawson, Valina; Dawson, Ted M; Ko, Hanseok Seok.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 4, 23.01.2018, p. 798-803.

Research output: Contribution to journalArticle

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AU - Bandaru, Veera Venkata Ratnam

AU - Yin, Xiling

AU - Rhee, Peter

AU - Karuppagounder, Senthilkumar

AU - Kwon, Seung Hwan

AU - Lee, Hojae

AU - Mao, Xiaobo

AU - Kim, Donghoon

AU - Pandey, Akhilesh

AU - Lee, Gabsang

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