title: A differential autophagy-dependent response to DNA double-strand breaks in bone marrow mesenchymal stem cells from sporadic ALS patients.
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 proved to be differentially expressed in the brain, spinal cord and muscle of the SOD1G93AALS 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 investigated the ALS-hMSC response to oxidative DNA damage 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.
authors.affiliation: Laboratory for Neurodegenerative Diseases and Personalized Medicine, Department of Cell Research and Immunology, The George S. Wise Faculty for Life Sciences, Sagol School of Neurosciences, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
authors.forename: Shane
authors.initials: S
authors.lastname: Wald-Altman
authors.affiliation: Laboratory for Neurodegenerative Diseases and Personalized Medicine, Department of Cell Research and Immunology, The George S. Wise Faculty for Life Sciences, Sagol School of Neurosciences, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
authors.forename: Edward
authors.initials: E
authors.lastname: Pichinuk
authors.affiliation: Department of Neurology, Hadassah-Hebrew University Medical Center, Ein Kerem, Jerusalem 91120, Israel.
authors.forename: Or
authors.initials: O
authors.lastname: Kakhlon
authors.affiliation: Laboratory for Neurodegenerative Diseases and Personalized Medicine, Department of Cell Research and Immunology, The George S. Wise Faculty for Life Sciences, Sagol School of Neurosciences, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel miguelw@tauex.tau.ac.il.
authors.forename: Miguel
authors.identifier: 0000-0001-5721-653X
authors.initials: M
authors.lastname: Weil
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D001343:Autophagy; D001854:Bone Marrow Cells / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*
keywords: ALS; Autophagy; DNA damage response; Human mesenchymal stem cell