Role of non-neuronal cells in the death of neuronal cells in ALS and neurodegeneration by Serge Przedborski
Role of non-neuronal cells in the death of neuronal cells in ALS and neurodegeneration
Cell-to-cell communications are critical determinants of pathophysiological phenotypes, but methodologies for their systematic elucidation are lacking. During this lecture, an integrative, systems biology approach that combines proteomics and regulatory network analysis to elucidate ligand-mediated interactions between distinct cellular compartments, will be discussed. It will be shown how such an approach could help unraveling the non-cell autonomous basis of neurodegeneration by using an experimental model of amyotrophic lateral sclerosis (ALS), in which astrocytes expressing mutant superoxide dismutase-1 (mutSOD1) kill wild-type motor neurons (MNs). Integrative analysis identified the interaction between astrocyte-released N-terminal fragments of amyloid precursor protein (APP) and death receptor-6 (DR6) on MNs as the top predicted ligand-receptor pair. The inferred pathogenic role of APP and/or DR6 was confirmed in vitro in both human sporadic and mouse familial ALS models, and in transgenic mutSOD1 mice with DR6 knockdown in MNs. Importantly, the proposed methodology is not restricted to this biological context and could be generalized to a variety of other non-cell-autonomous communication mechanisms.
Dr. Przedborski’s is the Page and William Black Professor of Neurology (in Pathology and Cell Biology) and the Chief of the Movement Disorders Division and the Vice-Chair of Research in the Department of Neurology as well as the Co-Director of Motor Neuron Center and the Director of the Columbia Translational Neuroscience Initiative. He received his MD degree and his PhD degree in Neurological Sciences from the Université Libre de Bruxelles in Belgium and did his Postdoctoral training at Columbia University, where he joined the faculty in 1991.
Dr. Przedborski’s research is geared toward unraveling the molecular basis of neurodegeneration and devising therapeutic strategies to hinder the processes that cause neuronal death, the source of many debilitating disorders. To that end, his laboratory has concentrated its research efforts on the mouse models of amyotrophic lateral sclerosis (ALS) and Parkinson’s disease to unravel the contribution of non-neuronal cells such as astrocytes and microglia to the demise of neighboring neuronal cells in neurodegenerative disorders.
To date, Dr Przedborski has coauthored more than 250 papers and fifteen books and book chapters. He has been the recipient of several Awards and Named-Lectures in recognition of his work in ALS and PD. Since he became a Columbia University faculty, his research has been consistently supported by federal grants from both NIH and the DoD as well as by several private agencies including ProjectALS and the Parkinson Foundation. Dr. Przedborski is a Reviewing Editor for eLife and a former Senior Editor for the Journal of Neuroscience and an Associate Editor of Movement Disorders. He has also been a members of several NIH study sections and currently serves as an ad hoc reviewer for the NIH, the Veterans Administration, the Department of Defense, the Canadian Medical Research Council, and his a regular reviewer for numerous medical journals including Science, Nature, Nature Neuroscience, Neuron, the New England Journal of Medicine, and the Proceedings of the National Academy of Science USA.