UMMS Affiliation
Department of Neurology
Publication Date
2020-08-06
Document Type
Article
Disciplines
Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Lipids | Nervous System | Nervous System Diseases | Neurology | Neuroscience and Neurobiology | Nutritional and Metabolic Diseases
Abstract
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.
Keywords
Lipid binding, Neuroprotection, Parkinson’s disease, Sandhoff disease, α-Synuclein, β-Hexosaminidase
Rights and Permissions
Copyright © The Author(s) 2020. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
DOI of Published Version
10.1186/s40478-020-01004-6
Source
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
Journal/Book/Conference Title
Acta neuropathologica communications
Related Resources
PubMed ID
32762772
Repository Citation
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 Publications by UMMS Authors. https://doi.org/10.1186/s40478-020-01004-6. Retrieved from https://escholarship.umassmed.edu/oapubs/4303
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Lipids Commons, Nervous System Commons, Nervous System Diseases Commons, Neurology Commons, Neuroscience and Neurobiology Commons, Nutritional and Metabolic Diseases Commons