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A differential autophagy dependent response to DNA-double strand brakes in bone marrow mesenchymal stem cells from sporadic ALS patients
Amyotrophic Lateral Sclerosis (ALS) is an incurable motor neurodegenerative disease caused by a diversity of genetic and environmental factors leading to neuromuscular degeneration and pathophysiological implications in non-neural systems. Our previous work showed abnormal transcriptional expression...
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Published in: | Disease models & mechanisms 2017-01 |
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Main Authors: | , , , |
Format: | Article |
Language: | English |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Amyotrophic Lateral Sclerosis (ALS) is an incurable motor neurodegenerative disease caused by a diversity of genetic and environmental factors leading to neuromuscular degeneration and pathophysiological implications in non-neural systems. Our previous work showed abnormal transcriptional expression levels of biomarker genes in non-neuronal cell samples from ALS patients. The same genes proved to be differentially expressed in brain, spinal cord and muscle of the SOD1G93A ALS mouse model. These observations support the pathophysiological relevance of the ALS biomarkers discovered in human mesenchymal stem cells (hMSC) isolated from bone marrow samples of ALS patients (ALS-hMSC). Here we demonstrate that ALS-hMSC are also a useful patient based model to study intrinsic cell molecular mechanisms of the disease. We investigated the ALS-hMSC response to oxidative DNA damage exerted by neocarzinostatin (NCS)-mediated DNA double-strand breaks (DSB). We found that the ALS-hMSC responded to this stress differently than cells from healthy controls (HC-hMSC). Interestingly, we found that ALS-hMSC cell death, in response to DSB, was dependent on autophagy, initialized by an increase of p-AMPK and blocked by the class III PI3K and autophagy inhibitor 3-methyladenine (3MeA). ALS-hMSC cell death in response to DSB 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 hMSC. This mechanism may also be relevant to the most affected tissues in ALS. Hence, our approach might be opening avenues for new therapies at the personalized level for ALS. |
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ISSN: | 1754-8403 1754-8411 |
DOI: | 10.1242/dmm.027938 |