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

ABSTRACT: Sandhoff disease (SD) is a lysosomal storage disease, caused by loss of ?-hexosaminidase (HEX) activity resulting in the accumulation of ganglioside GM2. There are shared features between SD and Parkinson's disease (PD). ?-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.

SUBMITTER: Brekk OR

PROVIDER: S-EPMC7409708 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Brekk Oeystein R OR Korecka Joanna A JA Crapart Cecile C CC Huebecker Mylene M MacBain Zachary K ZK Rosenthal Sara Ann SA Sena-Esteves Miguel M Priestman David A DA Platt Frances M FM Isacson Ole O Hallett Penelope J PJ

Acta neuropathologica communications 20200806 1

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 fo ...[more]

PMID: 32762772

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Project description:Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid, play a crucial role in cytoprotection by attenuating oxidative stress, inﬂammation and apoptosis. EETs are rapidly metabolised in vivo by the soluble epoxide hydrolase (sEH). Increasing the half life of EETs by inhibiting the sEH enzyme is a novel strategy for neuroprotection. In the present study, sEH inhibitors APAU was screened in silico and further evaluated for their antiparkinson activity against rotenone (ROT) induced neurodegeneration in N27 dopaminergic cell line and Drosophila melanogaster model of Parkinson disease (PD). In the in vitro study cell viability (MTT and LDH release assay), oxidative stress parameters (total intracellular ROS, hydroperoxides, protein oxidation, lipid peroxidation, superoxide dismutase, catalase, glutathione peroxidise, glutathione reductase, glutathione, total antioxidant status, mitochondrial complex-1activity and mitochondrial membrane potential), inflammatory markers (IL-6, COX-1 and COX-2), and apoptotic markers (JNK, phospho-JNK, c-jun, phospho-c-jun, pro and active caspase-3) were assessed to study the neuroprotective effects. In vivo activity of APAU was assessed in Drosophila melanogaster by measuring survival rate, negative geotaxis, oxidative stress parameters (total intracellular ROS, hydroperoxides, glutathione levels) were measured. Dopamine and its metabolites were estimated by LC-MS/MS analysis. In the in silico study the molecule, APAU showed good binding interaction at the active site of sEH (PDB: 1VJ5). In the in vitro study, APAU significantly attenuated ROT induced changes in oxidative, pro-inflammatory and apoptotic parameters. In the in vivo study, APAU significantly attenuates ROT induced changes in survival rate, negative geotaxis, oxidative stress, dopamine and its metabolites levels (p < 0.05). Our study, therefore, concludes that the molecule APAU, has significant neuroprotection benefits against rotenone induced Parkinsonism.

Dataset Information

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

Publications

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

Similar Datasets

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