期刊
CELLS
卷 11, 期 7, 页码 -出版社
MDPI
DOI: 10.3390/cells11071230
关键词
aromatic-turmerone; dopaminergic neurons; microglia; Nrf2
类别
资金
- MEXT, Japan [19K07123, 19K06899]
- program for Brain/MINDS from AMED, Japan [JP20dm0207057, JP21dm0207111]
- Joint Research Program of the Biosignal Research Center, Kobe University [191005]
- JSPS KAKENHI
- Grants-in-Aid for Scientific Research [19K07123, 19K06899] Funding Source: KAKEN
This study found that D-cysteine enhances CMA activity by generating hydrogen sulfide and regulating CMA activity via Nrf2 activation.
Chaperone-mediated autophagy (CMA) is a pathway in the autophagy-lysosome protein degradation system. CMA impairment has been implicated to play a role in spinocerebellar ataxia (SCA) pathogenesis. D-cysteine is metabolized by D-amino acid oxidase (DAO), leading to hydrogen sulfide generation in the cerebellum. Although D-cysteine alleviates the disease phenotypes in SCA-model mice, it remains unknown how hydrogen sulfide derived from D-cysteine exerts this effect. In the present study, we investigated the effects of D-cysteine and hydrogen sulfide on CMA activity using a CMA activity marker that we have established. D-cysteine activated CMA in Purkinje cells (PCs) of primary cerebellar cultures where DAO was expressed, while it failed to activate CMA in DAO-deficient AD293 cells. In contrast, Na2S, a hydrogen sulfide donor, activated CMA in both PCs and AD293 cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) is known to be activated by hydrogen sulfide and regulate CMA activity. An Nrf2 inhibitor, ML385, prevented CMA activation triggered by D-cysteine and Na2S. Additionally, long-term treatment with D-cysteine increased the amounts of Nrf2 and LAMP2A, a CMA-related protein, in the mouse cerebellum. These findings suggest that hydrogen sulfide derived from D-cysteine enhances CMA activity via Nrf2 activation.
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