Characterizing Vulnerable Cell Types in C9orf72-FTD

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Project Summary/Abstract C9orf72 expansion mutations are the most common genetic cause of frontotemporal dementia (C9-FTD), a fatal and incurable neurodegenerative disease. C9-FTD is most commonly neuropathologically characterized by frontotemporal lobar degeneration (C9-FTLD) and the accumulation of phospho-TDP-43 (pTDP-43) inclusions in neurons and glia. In C9-FTLD, the medial orbitofrontal cortex (mOFC) is affected early in the disease course, and individuals with mOFC lesions phenocopy patients with FTD, suggesting that mOFC dysfunction impacts FTD clinical phenotypes. In disease, the mOFC exhibits pTDP-43 inclusions, neuronal degeneration, and neuroinflammation, including the development of pathologic microglia. In other diseases, pathologic microglia increase extracellular glutamate and induce death in excitatory neurons. However, these factors’ relative contributions to C9-FTLD pathogenesis are not well understood, and the molecular profiles of degenerating neurons (termed vulnerable neurons) and pathologic microglia in the mOFC are unknown. We hypothesize that in C9-FTLD, pathologic microglia contribute to the selective degeneration of vulnerable populations of excitatory neurons, resulting in dementia. This proposal aims to use transcriptomic methods to identify vulnerable neuron and pathologic microglia subtypes and characterize their molecular profiles, spatial distributions, and interactions that may be contributing to disease progression. To this end, Aim #1 will use single-nucleus RNA sequencing to identify and characterize the pathologic microglia subtypes that arise and the vulnerable neuron subtypes that degenerate in C9-FTLD. Cellular proximity is the basis for intercellular interactions, and Aim #2 will use spatial transcriptomics to identify where these pathologic microglia and vulnerable neurons are spatially distributed as well as their spatial proximities in relation to each other and to pTDP-43 inclusions. A better understanding of how C9-FTLD changes neurons’ and microglia’s gene expression patterns, their spatial distributions, and their interactions may lead to strategies to protect cells from disease and patients from dementia. These studies will emphasize how pathologic microglia can contribute to neurodegeneration, enabling the development of microglia-targeted therapies for C9-FTD and other neurodegenerative diseases. Through this project, I will develop expertise in the use of histological and computational techniques. My sponsor, Dr. Edward Lee, is committed to my training and success as a physician-scientist.