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

著者: Sangjune Kim, Seung Pil Yun, Saebom Lee, George K. E. Umanah, Veera Venkata Ratnam Bandaru, Xiling Yin, Peter Rhee, Senthilkumar S. Karuppagounder, Seung‐Hwan Kwon, Hojae Lee, Xiaobo Mao, Donghoon Kim, Akhilesh Pandey, Gabsang Lee, Valina L. Dawson, Ted M. Dawson, Han Seok Ko - Proceedings of the National Academy of Sciences, PNAS 2018 被引用: 177

Significance Recent studies have identified a helically folded tetramer as the major normal structure of α-synuclein (α-syn) and that the tetramer resists aggregation. However, the underlying mechanisms that regulate the formation of α-syn tetramers remain elusive. Our study shows that mutations in glucocerebrosidase 1 ( GBA1 ) and depletion-induced GBA1 deficiency leading to accumulation of glycosphingolipids (GSLs) are sufficient to cause destabilization of α-syn tetramers and increase the susceptibility of human dopaminergic neurons to cytotoxicity due to exposure to pathologic α-syn fibrils. Therefore, maintaining GBA1 activity and reducing GSLs are potentially important in reducing misfolding and pathogenic aggregation of α-syn in Parkinson’s disease.