A differential autophagy-dependent response to DNA doublestrand breaks in bone marrow mesenchymal stem cells from sporadic ALS patients

Shane Wald-Altman, Edward Pichinuk, Or Kakhlon, Miguel Weil*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    4 Scopus citations

    Abstract

    Amyotrophic lateral sclerosis (ALS) is an incurable motor neurodegenerative disease caused by a diversity of genetic and environmental factors that leads to neuromuscular degeneration and has pathophysiological implications in non-neural systems. Our previous work showed abnormal levels of mRNA expression for biomarker genes in non-neuronal cell samples from ALS patients. The same genes provedto bedifferentiallyexpressed in the brain, spinal cord and muscle of the SOD1G93A ALS mouse model. These observations support the idea that there is a pathophysiological relevance for the ALS biomarkers discovered in human mesenchymal stem cells (hMSCs) isolated from bone marrow samples of ALS patients (ALS-hMSCs). Here, we demonstrate that ALS-hMSCs are also a useful patient-based model to study intrinsic cell molecular mechanisms of the disease. We investigatedtheALS-hMSC responseto oxidative DNAdamage exerted by neocarzinostatin (NCS)-induced DNA double-strand breaks (DSBs). We found that the ALS-hMSCs responded to this stress differently from cells taken from healthy controls (HC-hMSCs). Interestingly, we found that ALS-hMSC death in response to induction of DSBs was dependent on autophagy, which was initialized by an increase of phosphorylated (p)AMPK, and blocked by the class III phosphoinositide 3-kinase (PI3K) and autophagy inhibitor 3-methyladenine (3MeA). ALS-hMSC death in response to DSBs was not apoptotic as it was caspase independent. This unique ALS-hMSC-specific response to DNA damage emphasizes the possibility that an intrinsic abnormal regulatory mechanism controlling autophagy initiation exists in ALS-patient-derived hMSCs. This mechanism may also be relevant to the most-affected tissues in ALS. Hence, our approach might open avenues for new personalized therapies for ALS.

    Original languageAmerican English
    Pages (from-to)645-654
    Number of pages10
    JournalDMM Disease Models and Mechanisms
    Volume10
    Issue number5
    DOIs
    StatePublished - 1 May 2017

    Bibliographical note

    Publisher Copyright:
    © 2017. Published by The Company of Biologists Ltd.

    Keywords

    • ALS
    • Autophagy
    • DNA damage response
    • Human mesenchymal stem cell

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