Stress-induced precocious aging in PD-patient iPSC-derived NSCs may underlie the pathophysiology of Parkinson’s disease

• Published in: Cell death & disease 2019-02, Vol.10 (2), p.105, Article 105
• Main Authors: Zhu, Liang, Sun, Chenxi, Ren, Jie, Wang, Guangming, Ma, Rongjie, Sun, Lixin, Yang, Danjing, Gao, Shane, Ning, Ke, Wang, Zhigang, Chen, Xu, Chen, Shengdi, Zhu, Hongwen, Gao, Zhengliang, Xu, Jun
• Format: Article
• Language: English
• Subjects: 101/28; 14/19; 14/34; 14/63; 38/77; 42/100; 42/89; 631/532/2182; 631/80/39/2346; 631/80/509; 692/699/375/1718; 82/80; 96/100; 96/109; Acetylation; Adult; Age; Aging; Animal models; Antibodies; Autophagy - genetics; Autophagy - radiation effects; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Differentiation; Cellular Senescence; DNA Damage; Dopamine receptors; Dopaminergic Neurons - metabolism; Humans; Immunology; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Inhibitory postsynaptic potentials; Life Sciences; Male; MAP kinase; Mitochondria; Movement disorders; Mutation; Neural Stem Cells - metabolism; Neural Stem Cells - physiology; Neural Stem Cells - radiation effects; Neurodegeneration; Neurodegenerative diseases; Oxidative stress; Oxidative Stress - physiology; p38 Mitogen-Activated Protein Kinases - metabolism; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Pathophysiology; Protein folding; SIRT1 protein; Sirtuin 1 - metabolism; Substantia nigra; Therapeutic applications; Young Adult
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1313-y

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.