| RRC ID |
74704
|
| 著者 |
Ren M, Yang Y, Heng KHY, Ng LY, Chong CY, Ng YT, Gorur-Shandilya S, Lee RMQ, Lim KL, Zhang J, Koh TW.
|
| タイトル |
MED13 and glycolysis are conserved modifiers of α-synuclein-associated neurodegeneration.
|
| ジャーナル |
Cell Rep
|
| Abstract |
α-Synuclein (α-syn) is important in synucleinopathies such as Parkinson's disease (PD). While genome-wide association studies (GWASs) of synucleinopathies have identified many risk loci, the underlying genes have not been shown for most loci. Using Drosophila, we screened 3,471 mutant chromosomes for genetic modifiers of α-synuclein and identified 12 genes. Eleven modifiers have human orthologs associated with diseases, including MED13 and CDC27, which lie within PD GWAS loci. Drosophila Skd/Med13 and glycolytic enzymes are co-upregulated by α-syn-associated neurodegeneration. While elevated α-syn compromises mitochondrial function, co-expressing skd/Med13 RNAi and α-syn synergistically increase the ratio of oxidized-to-reduced glutathione. The resulting neurodegeneration can be suppressed by overexpressing a glycolytic enzyme or treatment with deferoxamine, suggesting that compensatory glycolysis is neuroprotective. In addition, the functional relationship between α-synuclein, MED13, and glycolytic enzymes is conserved between flies and mice. We propose that hypoxia-inducible factor and MED13 are part of a druggable pathway for PD.
|
| 巻・号 |
41(12)
|
| ページ |
111852
|
| 公開日 |
2022-12-20
|
| DOI |
10.1016/j.celrep.2022.111852
|
| PII |
S2211-1247(22)01744-2
|
| PMID |
36543134
|
| MeSH |
Animals
Drosophila / metabolism
Drosophila Proteins* / genetics
Drosophila Proteins* / metabolism
Eye Proteins / metabolism
Genome-Wide Association Study
Glycolysis
Humans
Mediator Complex / metabolism
Mice
Parkinson Disease* / metabolism
Synucleinopathies*
alpha-Synuclein / genetics
alpha-Synuclein / metabolism
|
| IF |
8.109
|
| リソース情報 |
| ショウジョウバエ |
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