Upregulating β-hexosaminidase activity in rodents prevents α-synuclein lipid associations and protects dopaminergic neurons from α-synuclein-mediated neurotoxicity

Acta Neuropathologica Communications

Miguel Sena-Esteves¹  Mylene Huebecker²  Frances M. Platt²  David A. Priestman²  Ole Isacson³  Penelope J. Hallett³  Sara Ann Rosenthal³  Oeystein R. Brekk³  Cecile C. Crapart³  Zachary K. MacBain³  Joanna A. Korecka³ 

[1] Department of Neurology, University of Massachusetts Medical School;Department of Pharmacology, University of Oxford;Neuroregeneration Institute, McLean Hospital / Harvard Medical School;

关键词: α-Synuclein;    β-Hexosaminidase;    Sandhoff disease;    Parkinson’s disease;    Neuroprotection;    Lipid binding;   

DOI  :  10.1186/s40478-020-01004-6

来源: DOAJ

【 摘 要 】

Abstract Sandhoff disease (SD) is a lysosomal storage disease, caused by loss of β-hexosaminidase (HEX) activity resulting in the accumulation of ganglioside GM2. There are shared features between SD and Parkinson’s disease (PD). α-synuclein (aSYN) inclusions, the diagnostic hallmark sign of PD, are frequently found in the brain in SD patients and HEX knockout mice, and HEX activity is reduced in the substantia nigra in PD. In this study, we biochemically demonstrate that HEX deficiency in mice causes formation of high-molecular weight (HMW) aSYN and ubiquitin in the brain. As expected from HEX enzymatic function requirements, overexpression in vivo of HEXA and B combined, but not either of the subunits expressed alone, increased HEX activity as evidenced by histochemical assays. Biochemically, such HEX gene expression resulted in increased conversion of GM2 to its breakdown product GM3. In a neurodegenerative model of overexpression of aSYN in rats, increasing HEX activity by AAV6 gene transfer in the substantia nigra reduced aSYN embedding in lipid compartments and rescued dopaminergic neurons from degeneration. Overall, these data are consistent with a paradigm shift where lipid abnormalities are central to or preceding protein changes typically associated with PD.

【 授权许可】

Unknown