Biomedical Seminars Calendar –

School of Medicine Home > Education > Biomedical Seminars

Abstract: As our population continues to age, neurodegenerative diseases are becoming more prevalent. These truly disastrous human diseases include Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease). These diseases share a common feature in protein misfolding and aggregation. Understanding, at a mechanistic level, the cellular consequences of protein misfolding will help to suggest potential strategies for therapeutic intervention. We use the baker’s yeast, Saccharomyces cerevisiae, as a simple, yet powerful, model system to study the cell biology underpinning protein-misfolding diseases. Our long-term goal is to identify the critical genes and cellular pathways affected by misfolded human disease proteins. We have focused on the ALS disease proteins TDP-43 and FUS/TLS and have used yeast models to define novel disease mechanisms and have extended our findings into animal models and even recently into human patients. We recently discovered mutations in one of the human homologs of a hit from our yeast TDP-43 modifier screen in ALS patients. Mutations in this gene are relatively common (~5% of cases) making it one of the most common genetic risk factors for ALS discovered to date. This underscores the power of such simple model systems to help reveal novel insight into human disease. These screens are also providing new and completely unexpected potential drug targets – another hit from one the TDP-43 modifier screens is a gene encoding lariat debranching enzyme and we discovered that inhibiting this enzyme potently suppresses TDP-43 toxicity in yeast and in mammalian neurons. Launching from these studies in yeast to test known ALS disease genes, we have also been using yeast as a discovery platform to predict novel ALS disease genes based on functional properties (for example, the presence of a prion-like domain) and to combine this approach with human genetics and next generation sequencing to further define the complex genetic landscape of ALS. We anticipate that our novel approach will be broadly applicable to other human disease situations, many of which are deeply rooted in basic biology.

Department:  Biology

Contact: Maria Magana-Lopez | 650-723-2413 | mmagana@stanford.edu

Presenter(s):

• Aaron Gitler Stanford University

© 2019 Stanford University School of Medicine   |  Terms of Use   |   Maps   |   Contacts   |   Jobs   |   Lane Medical Library