Department of Neurology
Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Lipids | Nervous System | Nervous System Diseases | Neurology | Neuroscience and Neurobiology | Nutritional and Metabolic Diseases
Sandhoff disease (SD) is a lysosomal storage disease, caused by loss of beta-hexosaminidase (HEX) activity resulting in the accumulation of ganglioside GM2. There are shared features between SD and Parkinson's disease (PD). alpha-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.
Lipid binding, Neuroprotection, Parkinson’s disease, Sandhoff disease, α-Synuclein, β-Hexosaminidase
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DOI of Published Version
Brekk OR, Korecka JA, Crapart CC, Huebecker M, MacBain ZK, Rosenthal SA, Sena-Esteves M, Priestman DA, Platt FM, Isacson O, Hallett PJ. Upregulating β-hexosaminidase activity in rodents prevents α-synuclein lipid associations and protects dopaminergic neurons from α-synuclein-mediated neurotoxicity. Acta Neuropathol Commun. 2020 Aug 6;8(1):127. doi: 10.1186/s40478-020-01004-6. PMID: 32762772; PMCID: PMC7409708. Link to article on publisher's site
Acta neuropathologica communications
Brekk OR, Korecka JA, Crapart CC, Huebecker M, MacBain ZK, Rosenthal SA, Sena-Esteves M, Priestman DA, Platt FM, Isacson O, Hallett PJ. (2020). Upregulating beta-hexosaminidase activity in rodents prevents alpha-synuclein lipid associations and protects dopaminergic neurons from alpha-synuclein-mediated neurotoxicity. Open Access Articles. https://doi.org/10.1186/s40478-020-01004-6. Retrieved from https://escholarship.umassmed.edu/oapubs/4303
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This work is licensed under a Creative Commons Attribution 4.0 License.
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