Zhu, L., Sun, C., Ren, J. et al. (12 more authors) (2019) Stress-induced precocious aging in PD-patient iPSC-derived NSCs may underlie the pathophysiology of Parkinson's disease. Cell Death and Disease, 10 (2). 105. ISSN 2041-4889
Abstract
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019. The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
Keywords: | Macroautophagy; Neural stem cells; Parkinson's disease; Senescence |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number MEDICAL RESEARCH COUNCIL MR/K008943/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 07 Mar 2019 11:47 |
Last Modified: | 20 May 2024 09:22 |
Status: | Published |
Publisher: | Springer Nature [academic journals on nature.com] |
Refereed: | Yes |
Identification Number: | 10.1038/s41419-019-1313-y |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:142350 |