| Autor: |
Zhu L; East Hospital, Tongji University School of Medicine, Shanghai, China., Sun C; East Hospital, Tongji University School of Medicine, Shanghai, China., Ren J; East Hospital, Tongji University School of Medicine, Shanghai, China., Wang G; East Hospital, Tongji University School of Medicine, Shanghai, China., Ma R; East Hospital, Tongji University School of Medicine, Shanghai, China., Sun L; East Hospital, Tongji University School of Medicine, Shanghai, China., Yang D; East Hospital, Tongji University School of Medicine, Shanghai, China., Gao S; East Hospital, Tongji University School of Medicine, Shanghai, China., Ning K; East Hospital, Tongji University School of Medicine, Shanghai, China.; Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK., Wang Z; Shanghai Myfun Medical Cosmetology Hospital, Shanghai, China., Chen X; Shanghai Eighth People's Hospital Affiliated to Jiangsu University, Shanghai, China., Chen S; Department of Neurology and Institue of Neurology, Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China. ruijincsd@126.com., Zhu H; Tianjin Hospital, Tianjin Academy of Integrative Medicine, Tianjin, China. hongwen_zhu@hotmail.com., Gao Z; Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. zhengliang_gao@tongji.edu.cn.; Advanced Institute of Translational Medicine, Tongji University School of Medicine, Shanghai, China. zhengliang_gao@tongji.edu.cn., Xu J; East Hospital, Tongji University School of Medicine, Shanghai, China. 1900912273@qq.com. |
| Abstrakt: |
Parkinson's disease (PD) is an aging-related degenerative disorder arisen from the loss of dopaminergic neurons in substantia nigra. Although many genetic mutations have been implicated to be genetically linked to PD, the low incidence of familial PD carried with mutations suggests that there must be other factors such as oxidative stress, mitochondrial dysfunction, accumulation of misfolded proteins, and enhanced inflammation, which are contributable to the pathophysiology of PD. The major efforts of current research have been devoted to unravel the toxic effect of multiple factors, which directly cause the degeneration of dopaminergic neurons in adulthood. Until recently, several studies have demonstrated that NSCs had compromised proliferation and differentiation capacity in PD animal models or PD patient-derived iPS models, suggesting that the pathology of PD may be rooted in some cellular aberrations at early developmental stage but the mechanism remains to be elusive. Based on the early-onset PD patient-specific iPSCs, we found that PD-patient iPSC-derived NSCs were more susceptible to stress and became functionally compromised by radiation or oxidative insults. We further unraveled that stress-induced SIRT1 downregulation leading to autophagic dysfunction, which were responsible for these deficits in PD-NSCs. Mechanistically, we demonstrated that stress-induced activation of p38 MAPK suppressed SIRT1 expression, which in turn augmented the acetylation of multiple ATG proteins of autophagic complex and eventually led to autophagic deficits. Our studies suggest that early developmental deficits may, at least partially, contribute to the pathology of PD and provide a new avenue for developing better therapeutic interventions to PD. |
