M. Levin

University of Saskatchewan Department of Neurology and Anatomy & Cell Biology
Michael C. Levin, M.D., is the inaugural Saskatchewan Multiple Sclerosis Endowed Clinical Research Chair and Professor of Neurology & Anatomy, Physiology, and Pharmacology at the University of Saskatchewan. He received his Bachelors’ of Science degree in chemistry with special honors at the George Washington University, his medical degree at Pennsylvania State University and basic neuroscience training at The Salk Institute. Dr. Levin completed his residency training in neurology at The New York Hospital/Cornell Medical Center – Memorial Sloan Kettering Cancer Center where Drs. Fred Plum and Jerry Posner mentored him during his residency including while he was chief neurology resident. He then completed his Multiple Sclerosis post-doctoral fellowship in the Neuroimmunology Branch at NIH with Dr. Henry McFarland and Steve Jacobson. He was recruited to the University of Tennessee in Memphis where he moved up the ranks to professor with tenure, led the MS clinic and developed a translational research program based on the role that dysfunctional RNA binding proteins play in the pathogenesis of neurodegeneration in MS and relevant MS models. His work has also been published in The New England Journal of Medicine, Nature Medicine, Annals of Neurology, Neurology, the Journal of Comparative Neurology, and the Journal of Neuroscience Research. Dr. Levin has received more than 30 awards for academic excellence and his work has been recognized by the National Multiple Sclerosis Society, American Academy of Neurology, the Society for Neuroscience and most recently, by a Canadian ‘Science, Technology, Innovation and Collaboration’ Award for the discovery of stress granules in brain tissue of an MS patient. Dr. Levin is married to his lovely wife for more than 29.2 years (and counting), Dr. Audrey Zucker-Levin, an academic physical therapist. He has two strappingly handsome sons and is an avid sailor and scuba diver.

Author Of 1 Presentation

Pathogenesis – Neurodegeneration Oral Presentation

YI01.03 - Inhibition of neuronal RNA binding protein dysfunction as a treatment for neurodegeneration in multiple sclerosis

Speakers
Presentation Number
YI01.03
Presentation Topic
Pathogenesis – Neurodegeneration
Lecture Time
11:24 - 11:36

Abstract

Background

Dysfunctional RNA binding proteins (RBPs), including heterogeneous nuclear ribonucleoprotein A1 (A1), are key pathological features of numerous neurologic diseases. Recently, evidence suggests that dysfunctional RBP biology, including mislocalization of the RBP from its homeostatic nuclear location to the cytoplasm, stress granule (SG) formation, and changes in RNA metabolism, are associated with neurodegeneration and worsened disease in multiple sclerosis (MS) and its models, such as experimental autoimmune encephalomyelitis (EAE).

Objectives

We hypothesized that correcting dysfunctional RBP biology with the nuclear export inhibitor, KPT-276, would restore A1 function by decreasing its nucleocytoplasmic mislocalization and reduce SG formation and neurodegeneration in spinal cord neurons from EAE animals as compared to vehicle controls.

Methods

C57BL/6 female mice were immunized with myelin oligodendrocyte glycoprotein (MOG35-55) to induce EAE. Upon reaching a clinical score of 2.5, mice were treated with KPT-276 (75 mg/kg, oral gavage) or vehicle control every other day for a total of six treatments. Two days following the final treatment, spinal cords were harvested and analyzed using immunofluorescence for A1 localization and SG formation in neurons as well as markers of neurodegeneration.

Results

EAE mice treated with KPT-276 showed a decrease in clinical score severity as compared to vehicle control EAE mice. Furthermore, mice treated with KPT-276 showed a significant reduction in the number of neurons with A1 mislocalization (*p=0.0351), the amount of A1 in the cytoplasm (*p=0.0341), and SG formation (*p=0.0208) as compared to vehicle mice. In the same areas of KPT-276 treated mice where there was a reduction in these features of dysfunctional RBP biology, there was a significant increase in the number of neurons indicative of increased neuronal survival (*p=0.0373).

Conclusions

These experiments suggest that modulating dysfunctional RBP biology through KPT-276 restores RBP function and is a potential therapeutic, which increases neuronal survival and decreases neurodegeneration and clinical disease severity.

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Moderator Of 1 Session

Free Communications Sun, Sep 13, 2020
Moderators
Session Type
Free Communications
Date
Sun, Sep 13, 2020
Time (ET)
13:00 - 14:15