University of California, San Francisco (UCSF)

Elucidating the Role of Oxidative Stress and pATM Signaling in Aging and Dementia

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As our lifespan continues to expand, several aging-related diseases including dementia are becoming increasingly common and will lead to devastating effects on our older population. Dementia is caused by progressive brain atrophy and impaired cognitive function. In several types of dementia neurons accumulate disease-specific proteins that are misfolded and aggregated, which is thought to underlie the neuronal death observed in these diseases.

Frontotemporal dementia (FTD) can present with a range of symptoms, including behavioral changes, apathy, and language difficulties due to the loss of neurons in particular brain regions. In behavioral variant FTD, a unique type of neuron (von Economo neurons or VENs) is lost early in the course of the disease. These neurons also feature early accumulation of aggregated proteins including tau and TDP-43. While we do not yet understand the mechanisms that underlie VEN-specific vulnerability in FTD, recent work suggests these neurons have high oxidative stress even during normal aging.

My work aims to elucidate the underlying cellular mechanisms that lead to tau and TDP-43 aggregation and neuronal loss in FTD. My work will examine the effects of oxidative stress on tau and TDP-43 misfolding in induced pluripotent stem cell (iPSC)-derived neurons and examine markers of oxidative stress in human FTLD histopathologic samples. I will subsequently use CRISPR-based screening techniques in iPSC-derived neurons to broadly examine the cellular pathways that contribute to protein aggregation and associated neuronal death. This work will improve our understanding of the genetic pathways that may contribute to neurodegeneration and provide novel genetic targets to slow or prevent dementia.