Benjamin Wolozin, M.D., Ph.D.

Benjamin Wolozin, Ph.D.
Professor of Pharmacology and Neurology
Department of Pharmacology

M.D., Ph.D.: Albert Einstein College of Medicine

Principal Investigator: Laboratory of Neurodegeneration

Research Interests

https://www.youtube.com/watch?v=LokutAVYhVw

Pathophysiology of Neurodegeneration: Molecular and cellular Biology

Overview: The goal of our research is to understand the mechanisms underlying neurodegenerative diseases, and then to use this understanding to develop novel interventions for disease.  Much of our research focuses on the central concept of regulated protein aggregation.  Protein aggregation in neurodegenerative diseases is classically thought to occur as an unwanted byproduct of protein misfolding.  Human genetic studies increasingly highlight the importance of RNA binding proteins in neurodegenerative diseases.  This is important because RNA binding proteins use protein aggregation as part of a normal regulated, physiological mechanism controlling protein synthesis.  Aggregated RNA binding proteins for stress granules, transport granules, P bodies, as well as participate in physiological functions, such as activity dependent protein synthesis.  Our research investigates the hypothesis that dysfunction of RNA granules causes neurodegenerative diseases.  Over active stress granule formation could contribute to neurodegeneration by altering patterns of protein synthesis and sequestering proteins that regulate cell death processes.  Hypo-active stress granules, leads to inadequate neuroprotection. 

Amyotrophic Lateral Sclerosis (ALS): Our studies of TDP-43 highlight the role of stress granules and other RNA granules in disease, and has driven our understanding of the role of regulated protein aggregation in disease.  TDP-43 is an RNA binding protein that is the predominant protein that accumulates in the cytoplasm of neurons during the course of the disease. We have found that stress causes TDP-43 to migrate from the nucleus to the cytoplasm to form RNA inclusions termed stress granules.  This work led to the discovery that the pathological inclusions in ALS co-localize with stress granule markers and enhance stress granule formation; we refer to these large, persistent stress granules as “pathological stress granules”.   Neurons also use RNA granules to transport mRNA from the soma to the synapse; the requirement for RNA granules in transport leads to large amounts of aggregated RNA binding proteins in the cytoplasm, which might account for the propensity of mutations in RNA binding proteins to cause neurodegenerative disease. Indeed, our recent studies show that disease-linked mutations in TDP-43 cause changes in neuronal RNA granules that are evident at the earliest stages in the disease process; RNA granules carrying mutant TDP-43 are enlarged and move abnormally slowly.

Novel Therapeutic Approaches to ALS:  Our ALS program also includes an exciting drug discovery effort.  We have identified numerous novel compounds that are able to prevent and possibly reverse formation of pathological stress granules caused by expression of TDP-43 carrying disease-linked mutations.    These compounds disperse pathological stress granules, solubilize mutant TDP-43 and send it back to the nucleus.  We are currently seeking to identify the targets of action of these compounds, and validating the actions of the compounds in animal models.

For information on our research in Alzheimer’s or Parkinson’s disease, click on “Other Research”.