GHSR deficiency exacerbates Parkinson's disease pathology by impairing autophagy
Xue Xiao,
Tingting Tang,
Mingxia Bi,
Jing Liu,
Mengru Liu,
Qian Jiao,
Xi Chen,
Chunling Yan,
Xixun Du,
Hong Jiang
Affiliations
Xue Xiao
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
Tingting Tang
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
Mingxia Bi
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
Jing Liu
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
Mengru Liu
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
Qian Jiao
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
Xi Chen
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
Chunling Yan
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
Xixun Du
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China; Corresponding author. Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
Hong Jiang
Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China; Qingdao Key Laboratory of Neurorehabilitation, University of Health and Rehabilitation Sciences, Qingdao, 266113, China; Corresponding author. Qingdao Key Laboratory of Neurorehabilitation, University of Health and Rehabilitation Sciences, Qingdao, 266113, China.
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.
