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Oct 23, 2018

Seminar - A Gene Therapy for Amyotropic Lateral Sclerosis (ALS, Lou Gehrig’s disease) Targeting RNA Homeostasis in Motor Neurons and Glia (Speaker: Professor Gregory Petsko)

Professor Gregory Petsko
Arthur J. Mahon Professor of Neuroscience
Brain and Mind Research Institute, Weill Cornell Medical College
New York, USA

Date: Tuesday, 23-October-2018
Time: 1:30 p.m.
Venue: Seminar Room 4, G/F, Laboratory Block,
Faculty of Medicine Building,
21 Sassoon Road, Pokfulam, Hong Kong

Summary:
FUS/TLS and TDP-43 are RNA binding proteins that, when mutated, can cause a subset of familial amyotrophic lateral sclerosis (fALS). Pathogenic mutant forms of FUS/TLS or TDP-43 traffic from the nucleus to, and form inclusions in, the cytoplasm of affected spinal motor neurons or glia. Cytosolic aggregates of TDP-43 or FUS are found in nearly all patients with the most common, idiopathic, sporadic form of the disease. We have created a yeast model of human FUS/TLS or TDP-43 expression that recapitulates multiple salient features of the pathology of the disease-causing mutant proteins. A genome-wide genetic screen using a yeast over-expression library has identified five yeast DNA/ RNA binding proteins, ECM32, NAM8, SBP1, SKO1, and VHR1, that rescue the toxicity of human FUS/TLS without changing its expression level, cytoplasmic translocation, or inclusion formation. Furthermore, hUPF1, a human homologue of ECM32, also rescues the toxicity of FUS/TLS or TDP-43 in a model of disease in mouse and in human motor neurons. Examination of the effect of FUS/TLS expression on the decay of selected mRNAs in yeast indicates that the nonsense-mediated decay pathway may be a major determinant of toxicity and/or suppression. Our work has led to a completely novel therapeutic strategy, that of UPF1 gene therapy, not to replace a disease gene but to bypass the effects of TDP-43 or FUS mislocalization. The results of implementing that strategy as we progress towards human clinical trials, expected to begin in 2019, will be presented.

 

ALL ARE WELCOME