GHSR deficiency exacerbates Parkinson's disease pathology by impairing autophagy

IF 10.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Redox Biology Pub Date : 2024-08-20 DOI:10.1016/j.redox.2024.103322
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Abstract

In Parkinson's disease (PD), exogenous ghrelin protects dopaminergic neurons through its receptor, growth hormone secretagogue receptor (GHSR). However, in contrast to the strikingly low levels of ghrelin, GHSR is highly expressed in the substantia nigra (SN). What role does GHSR play in dopaminergic neurons is unknown. In this study, using GHSR knockout mice (Ghsr−/− mice) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model, we found that GHSR deletion aggravated dopaminergic neurons degeneration, and the expression and activity of GHSR were significantly reduced in PD. Furthermore, we explored the potential mechanism that GHSR deficiency aggregated PD-related neurodegeneration. We showed that DEPTOR, a subunit of mTORC1, was overexpressed in Ghsr−/− mice, positively regulating autophagy and enhancing autophagy initiation. The expression of lysosomal markers was abnormal, implying lysosomal dysfunction. As a result, the damaged mitochondria could not be effectively eliminated, which ultimately exacerbated the injury of nigral dopaminergic neurons. In particular, we demonstrated that DEPTOR could be transcriptionally regulated by KLF4. Specific knockdown of KLF4 in dopaminergic neurons effectively alleviated neurodegeneration in Ghsr−/− mice. In summary, our results suggested that endogenous GHSR deletion-compromised autophagy by impairing lysosomal function, is a key contributor to PD, which provided ideas for therapeutic approaches involving the manipulation of GHSR.

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GHSR 缺乏症通过损害自噬作用加剧帕金森病的病理变化
在帕金森病(PD)中,外源性胃泌素通过其受体生长激素分泌受体(GHSR)保护多巴胺能神经元。然而,与胃泌素含量极低形成鲜明对比的是,GHSR 在黑质(SN)中却高度表达。GHSR 在多巴胺能神经元中扮演什么角色尚不清楚。本研究利用GHSR基因敲除小鼠(小鼠)和1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的帕金森病模型,发现GHSR缺失会加重多巴胺能神经元变性,并且在帕金森病中GHSR的表达和活性显著降低。此外,我们还探讨了 GHSR 缺乏导致 PD 相关神经变性聚集的潜在机制。我们发现,mTORC1的一个亚基DEPTOR在小鼠中过度表达,正向调节自噬并增强自噬的启动。溶酶体标志物表达异常,意味着溶酶体功能障碍。因此,受损的线粒体无法被有效清除,最终加剧了黑质多巴胺能神经元的损伤。我们特别证明了 DEPTOR 可受 KLF4 的转录调控。特异性敲除多巴胺能神经元中的 KLF4 能有效缓解小鼠的神经退行性变。总之,我们的研究结果表明,内源性GHSR缺失会损害溶酶体功能,从而影响自噬,这是导致帕金森病的一个关键因素,这为操纵GHSR的治疗方法提供了思路。
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来源期刊
Redox Biology
Redox Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
19.90
自引率
3.50%
发文量
318
审稿时长
25 days
期刊介绍: Redox Biology is the official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe. It is also affiliated with the International Society for Free Radical Research (SFRRI). This journal serves as a platform for publishing pioneering research, innovative methods, and comprehensive review articles in the field of redox biology, encompassing both health and disease. Redox Biology welcomes various forms of contributions, including research articles (short or full communications), methods, mini-reviews, and commentaries. Through its diverse range of published content, Redox Biology aims to foster advancements and insights in the understanding of redox biology and its implications.
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