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Merck
  • GBA deficiency promotes SNCA/α-synuclein accumulation through autophagic inhibition by inactivated PPP2A.

GBA deficiency promotes SNCA/α-synuclein accumulation through autophagic inhibition by inactivated PPP2A.

Autophagy (2015-09-18)
Ting-Ting Du, Le Wang, Chun-Li Duan, Ling-Ling Lu, Jian-Liang Zhang, Ge Gao, Xiao-Bo Qiu, Xiao-Min Wang, Hui Yang
摘要

Loss-of-function mutations in the gene encoding GBA (glucocerebrosidase, β, acid), the enzyme deficient in the lysosomal storage disorder Gaucher disease, elevate the risk of Parkinson disease (PD), which is characterized by the misprocessing of SNCA/α-synuclein. However, the mechanistic link between GBA deficiency and SNCA accumulation remains poorly understood. In this study, we found that loss of GBA function resulted in increased levels of SNCA via inhibition of the autophagic pathway in SK-N-SH neuroblastoma cells, primary rat cortical neurons, or the rat striatum. Furthermore, expression of the autophagy pathway component BECN1 was downregulated as a result of the GBA knockdown-induced decrease in glucocerebrosidase activity. Most importantly, inhibition of autophagy by loss of GBA function was associated with PPP2A (protein phosphatase 2A) inactivation via Tyr307 phosphorylation. C2-ceramide (C2), a PPP2A agonist, activated autophagy in GBA-silenced cells, while GBA knockdown-induced SNCA accumulation was reversed by C2 or rapamycin (an autophagy inducer), suggesting that PPP2A plays an important role in the GBA knockdown-mediated inhibition of autophagy. These findings demonstrate that loss of GBA function may contribute to SNCA accumulation through inhibition of autophagy via PPP2A inactivation, thereby providing a mechanistic basis for the increased PD risk associated with GBA deficiency.

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