A biophysical hypothesis for the initiation of spontaneous ALS

Dr Liam Holt 

Institute for Systems Genetics, New York University School of Medicine

The cause of sporadic ALS/FTD is unknown. A central, yet poorly explained neuropathological hallmark of Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS/FTD) is the aggregation and accumulation of disease-associated RNA binding proteins such as TDP-43 or hnRNPA2. In a small minority of cases of familial disease, mutations make these proteins prone to aggregation. However, the vast majority of cases are sporadic and the cell biological events that initiate protein aggregation and neurodegeneration are a mystery. We will look beyond mutations that only occur in a minority of cases and establish a new conceptual framework focusing on the biophysical underpinnings of sporadic disease. We hypothesize that mechanical changes to tissue and dysregulation of cellular metabolism together shift the biophysical properties of the intracellular environment, thereby perturbing the balance of molecular motion and assembly. I will discuss the evidence from the field pointing to this hypothesis and new technologies that we have developed to test these ideas.

Liam Holt attended the University of Bath, completed his Ph. D. at UCSF in 2009, and was then a Bowes Fellow at UC Berkeley. Liam is currently Associate Professor of Biochemistry and Molecular Pharmacology at New York University. His lab studies how mechanical compression affects cells, and how the physical properties of the cell interior affect biochemistry in both normal biology and disease. He is passionate about outreach and community: He cofounded Science Sketches (www.sciencesketches.org), an online dictionary of science videos now partnered with the Explorer’s Guide to Biology (www.explorebiology.org) and MBoC Journal; and Inspire Science (www.inspiresci.org), a symposium about maintaining happiness in a challenging career.

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Bobbie Claxton
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Online via Zoom