Membrane-bound ¦Á-synuclein interacts with glucocerebrosidase and inhibits enzyme activity

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• 作者：Thai Leong Yap^a ; Arash Velayati^b ; Ellen Sidransky^b ; ^{sidranse@mail.nih.gov} ; Jennifer C. Lee^a ; ^{leej4@mail.nih.gov}
• 关键词：¦Á-syn ; ¦Á-synuclein ; PD ; Parkinson disease ; LBs ; Lewy bodies ; GD ; Gaucher disease ; GCase ; glucocerebrosidase ; WT ; wild-type ; ¦Á-glu A ; acid ¦Á-glucosidase ; N15 ; ¦Á-syn peptide residues 1&ndash ; 15 ; C23 ; ¦Á-syn peptide residues 118&ndash ; 140 ; MES ; 2-(N-mor
• 刊名：Molecular Genetics and Metabolism
• 出版年：2013
• 出版时间：January, 2013
• 年：2013
• 卷：108
• 期：1
• 页码：56-64
• 全文大小：1238 K

文摘

Mutations in GBA, the gene encoding glucocerebrosidase, the lysosomal enzyme deficient in Gaucher disease increase the risk for developing Parkinson disease. Recent research suggests a relationship between glucocerebrosidase and the Parkinson disease-related amyloid-forming protein, ¦Á-synuclein; however, the specific molecular mechanisms responsible for association remain elusive. Previously, we showed that ¦Á-synuclein and glucocerebrosidase interact selectively under lysosomal conditions, and proposed that this newly identified interaction might influence cellular levels of ¦Á-synuclein by either promoting protein degradation and/or preventing aggregation. Here, we demonstrate that membrane-bound ¦Á-synuclein interacts with glucocerebrosidase, and that this complex formation inhibits enzyme function. Using site-specific fluorescence and F?rster energy transfer probes, we mapped the protein-enzyme interacting regions on unilamellar vesicles. Our data suggest that on the membrane surface, the glucocerebrosidase-¦Á-synuclein interaction involves a larger ¦Á-synuclein region compared to that found in solution. In addition, ¦Á-synuclein acts as a mixed inhibitor with an apparent IC₅₀ in the submicromolar range. Importantly, the membrane-bound, ¦Á-helical form of ¦Á-synuclein is necessary for inhibition. This glucocerebrosidase interaction and inhibition likely contribute to the mechanism underlying GBA-associated parkinsonism.