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.

中文翻译：

---

GHSR 缺乏通过损害自噬加剧帕金森病病理


在帕金森病 (PD) 中，外源性生长素释放肽通过其受体、生长激素促分泌素受体 (GHSR) 保护多巴胺能神经元。然而，与极低水平的生长素释放肽相反，GHSR 在黑质 (SN) 中高度表达。 GHSR 在多巴胺能神经元中发挥什么作用尚不清楚。在这项研究中，使用GHSR敲除小鼠（Ghsr−/−小鼠）和1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的PD模型，我们发现GHSR缺失加剧了多巴胺能神经元的变性，并且 GHSR 的表达和活性在 PD 中显着降低。此外，我们还探讨了 GHSR 缺乏聚集 PD 相关神经变性的潜在机制。我们发现 DEPTOR（mTORC1 的一个亚基）在 Ghsr−/− 小鼠中过度表达，正向调节自噬并增强自噬启动。溶酶体标志物表达异常，提示溶酶体功能障碍。结果，受损的线粒体无法有效消除，最终加剧了黑质多巴胺能神经元的损伤。特别是，我们证明了 DEPTOR 可以受 KLF4 转录调控。多巴胺能神经元中 KLF4 的特异性敲低有效减轻了 Ghsr−/− 小鼠的神经变性。总之，我们的结果表明，内源性 GHSR 缺失通过损害溶酶体功能而损害自噬，是 PD 的关键因素，这为涉及 GHSR 操纵的治疗方法提供了思路。