title: GBA deficiency promotes SNCA/α-synuclein accumulation through autophagic inhibition by inactivated PPP2A.
abstract: 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.
authors.affiliation: a Center of Parkinson Disease Beijing Institute for Brain Disorders; Key Laboratory for Neurodegenerative Disease of the Ministry of Education; Department of Neurobiology Capital Medical University ; Beijing , China.|b Key Laboratory of Cell Proliferation and Regulation Biology; Ministry of Education; College of Life Sciences; Beijing Normal University ; Beijing , China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Du
authors.affiliation: a Center of Parkinson Disease Beijing Institute for Brain Disorders; Key Laboratory for Neurodegenerative Disease of the Ministry of Education; Department of Neurobiology Capital Medical University ; Beijing , China.
authors.forename: Le
authors.initials: L
authors.lastname: Wang
authors.affiliation: a Center of Parkinson Disease Beijing Institute for Brain Disorders; Key Laboratory for Neurodegenerative Disease of the Ministry of Education; Department of Neurobiology Capital Medical University ; Beijing , China.
authors.forename: Chun-Li
authors.initials: CL
authors.lastname: Duan
authors.affiliation: a Center of Parkinson Disease Beijing Institute for Brain Disorders; Key Laboratory for Neurodegenerative Disease of the Ministry of Education; Department of Neurobiology Capital Medical University ; Beijing , China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Lu
authors.affiliation: a Center of Parkinson Disease Beijing Institute for Brain Disorders; Key Laboratory for Neurodegenerative Disease of the Ministry of Education; Department of Neurobiology Capital Medical University ; Beijing , China.
authors.forename: Jian-Liang
authors.initials: JL
authors.lastname: Zhang
authors.affiliation: a Center of Parkinson Disease Beijing Institute for Brain Disorders; Key Laboratory for Neurodegenerative Disease of the Ministry of Education; Department of Neurobiology Capital Medical University ; Beijing , China.
authors.forename: Ge
authors.initials: G
authors.lastname: Gao
authors.affiliation: b Key Laboratory of Cell Proliferation and Regulation Biology; Ministry of Education; College of Life Sciences; Beijing Normal University ; Beijing , China.
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Qiu
authors.affiliation: a Center of Parkinson Disease Beijing Institute for Brain Disorders; Key Laboratory for Neurodegenerative Disease of the Ministry of Education; Department of Neurobiology Capital Medical University ; Beijing , China.
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Wang
authors.affiliation: a Center of Parkinson Disease Beijing Institute for Brain Disorders; Key Laboratory for Neurodegenerative Disease of the Ministry of Education; Department of Neurobiology Capital Medical University ; Beijing , China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D005776:Gaucher Disease / Q000235:genetics; D015870:Gene Expression / Q000502:physiology; D005962:Glucosylceramidase / Q000172:deficiency; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051381:Rats; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: C497604:SNCA protein, human; C497605:Snca protein, mouse; C497606:Snca protein, rat; D051844:alpha-Synuclein; C517189:PPP2CA protein, human; C578496:PPP2CA protein, mouse; C514014:Ppp2ca protein, rat; D054648:Protein Phosphatase 2; D005962:Glucosylceramidase
keywords: Parkinson disease; autophagy; glucocerebrosidase; protein phosphatase 2A; α-synuclein