Pathology

Enzyme

Disease

Glucocerebrosidase

Alpha-synuclein

Biology

Gene

Induced pluripotent stem cell

Embryonic stem cell

Chemistry

Fibril

Synucleinopathies

Parkinson's disease

Tetramer

Mutation

Cell biology

Biochemistry

Medicine

Proceedings of the National Academy of Sciences

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.

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