UCSF

Neurodegenerative diseases are a major public health burden. There are only a few effective therapies because the underlying disease mechanisms are poorly understood. Tau aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer’s disease and frontotemporal dementia. There are causal disease variants of the tau-encoding gene, MAPT, and the presence of tau aggregates is highly correlated with disease progression. The molecular mechanisms linking pathological tau to neuronal dysfunction are not well understood. A major challenge for the tau field is a lack of clarity around tau’s normal function in development and disease and how these processes change in the context of causal disease variants or amyloid beta plaques.

To address these questions in an unbiased manner, we conducted multi-omic characterization of iPSC-derived neurons harboring the MAPT V337M mutation, which revealed major changes in regulators of axonogenesis. MAPT V337M neurons have increased axon branching. Pathogenic tau mutations have generally been assumed to act through a gain of toxic function, leading to therapeutic approaches aiming to lower tau levels that are currently in clinical trials. Surprisingly, we found that tau knockdown did not rescue axon branching in MAPT V337M neurons, and tau knockdown induced axon branching in MAPT WT neurons, strongly supporting a tau loss of function effect. Intriguingly, knockdown the tau-interacting protein MYO1B also increases axon branching in wild-type neurons without modifying axon branching in MAPT V337M neurons. We conclude that the FTD-associated tau mutation MAPT V337M drives major changes in neuronal differentiation and maturation caused by loss of tau function.