Speaker: Greg Sienski | Whitehead Institute for Biomedical Research/Sabatini Laboratory | Cambridge/MA
Title of the talk: Metabolic consequences of genetic variation
Host: Markus Landthaler
Alzheimer’s Disease (AD) is the most common neurodegenerative disease worldwide and currently affects more than 46 million people. As the etiology of AD remains unknown and no therapies exist, understanding the molecular abnormalities underlying AD is critical for the development of therapeutics. Genome-wide association studies have established that a coding mutation in the apolipoprotein APOE gene (called APOE4) triples AD risk and lowers the age of onset. How ApoE4 contributes to AD remains a mystery in the field.We established new models to study intracellular functions of APOE4 and dissected the biology of this major AD risk factor. Using combination of genome-wide screens, targeted genetics and metabolomics, we found that APOE4 perturbs lipid homeostasis in all models including astrocytes derived from human iPSCs. Subsequently, we found a metabolite that corrects all of the ApoE4-induced phenotypes and, moreover, uncouples the presence of ApoE4 from its cytotoxicity. Based on our data, we propose a mechanism of action for ApoE4 that explains many of the molecular pathologies found in AD patients.
You are all cordially invited to attend this talk. No registration required. This seminar will be held in English.