Abstract

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 relevant human cell types, we established a CRISPR -based platform for genetic screening in human iPSC-derived neurons, astrocytes and microglia. In an application relevant for Alzheimer’s Disease and other neurodegenerative diseases, we are using this platform to understand cellular mechanisms controlling the aggregation, spreading, and toxicity of the protein tau. Tau aggregates are a hallmark of Alzheimer’s Disease and tauopathies. Mutations in tau are linked to familial neurodegenerative diseases. However, we still lack consensus on the molecular mechanisms by which tau contributes to neurodegeneration. Intriguingly, different types of neurons show selective vulnerability to tau aggregation, suggesting that cellular pathways play a key role in controlling aggregation and resulting toxicity. A systematic understanding of these pathways would enable a mechanistic understanding of the disease processes and point to potential therapeutic targets. Our screens have identified roles for specific cellular pathways, including specific chaperones and co-chaperones, autophagy, mitochondrial function, and some factors with mostly uncharacterized function. We are using biochemistry and cell biology to clarify the mechanisms by which these factors control tau aggregation and toxicity, and to evaluate their potential as therapeutic targets.