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

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

Acta neuropathologica communications (2020-08-09)
Oeystein R Brekk, Joanna A Korecka, Cecile C Crapart, Mylene Huebecker, Zachary K MacBain, Sara Ann Rosenthal, Miguel Sena-Esteves, David A Priestman, Frances M Platt, Ole Isacson, Penelope J Hallett
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Mowiol® 4-88, Mw ~31,000
Sigma-Aldrich
Anti-GAPDH Antibody, from chicken, purified by affinity chromatography
Sigma-Aldrich
Naphthol AS-BI N-acetyl-β-D-glucosaminide, β-hexosaminidase substrate
Sigma-Aldrich
Anti-α-Synuclein Antibody, clone Syn211, ascites fluid, clone Syn211, Upstate®