Friday, November 22, 2024
11/22/2024
PROJECT SUMMARY / ABSTRACT Losses in protein homeostasis associated with accumulation of damaged, misfolded and aggregated proteins is a characteristic feature of aging and many age-related neurodegenerative diseases. We hypothesize that this may in part be driven by age-related dysfunctions in autophagy which establishes a prodromal process resulting in decreased protein homeostasis and subsequent neurodegeneration. Growing evidence suggests that reduced activity of transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, could underlie many neurodegenerative diseases. Based on these findings, we conducted a chemical screen in a neuronal cell line for chemical compounds that induce TFEB. We identified a series of compounds that induce TFEB and its targets to levels far exceeding that produced by the classic TFEB inducer rapamycin. Our lead compound `C1' was tested across a wide range of proteotoxic disease models including in the nematode C. elegans, in in vitro human neuronal tauopathy models, and in an in vivo mouse model of Parkinson's disease (PD). In conjunction with elevations in autophagic flux, the compound was found to prevent the formation of neurotoxic proteins aggregates and enhanced mitochondrial function. Subsequent genetic and biochemical analysis shows that C1 induces TFEB by acting as a “reverse agonist” of the nuclear hormone receptor DAF- 12/FXR, validated via the use of known modulators of DAF-12/FXR. Although FXR is best known for its ability to act in the liver and gut to maintain lipid homeostasis, it has recently been shown to be present in brain neurons although its role in here is currently unexplored. Our results highlight a novel previously uncharacterized role for FXR-TFEB signaling-mediated autophagy in age-associated neurodegenerative diseases. Based on these results, we hypothesize that neuronal FXR mechanistically acts to modulate levels of TFEB-mediated autophagy and as such constitutes a novel target for the treatment of age-related neurodegenerative diseases including Alzheimer's disease (AD). To test this hypothesis, we propose to determine whether: (1) FXR inhibition results in downstream TFEB signaling, triggering an increase in neuronal autophagy within neurons affected in AD and (2) prevents subsequent development of established AD-related pathologies. Proposed studies include analyses in both human iPSC-derived neurons and in brain tissues from an in vivo AD mouse model to interrogate features associated with human disease including progressive development of mitochondrial deficits, Aβ and tau neuropathology, losses in synapse integrity, and in mice, cognitive dysfunction.
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