Human genes associated with brain-related diseases are being discovered at an accelerating pace. A major challenge is the identification of the mechanisms through which these genes act, and of potential therapeutic strategies. To elucidate such mechanisms in human cells, we are leveraging a CRISPR-based platform for genetic screening that we recently co-developed. Our approach relies on CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa), in which a catalytically dead version of the bacterial Cas9 protein recruits transcriptional repressors or activators, respectively, to endogenous genes to control their expression, as directed by a small guide RNA (sgRNA). Complex libraries of sgRNAs enable us to conduct genome-wide loss-of-function and gain-of-function screens in mammalian cells. We have adapted this strategy for use in human iPSC-derived neurons and glia, enabling us to conduct genetic modifier screens for disease-relevant cellular phenotypes in patient-derived cells with familial mutations and isogenic CRISPR-corrected controls. Our first screens are uncovering cellular mechanisms controlling neuronal aggregation of the protein tau, which is a hallmark of Alzheimer’s Disease and other tauopathies.
A CRISPR Approach to Neurodegenerative Diseases
Assistant Professor, Institute for Neurodegenerative Diseases
University of California, San Francisco
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