Metal responsive transcription factors in neurodegeneration

Dementias are etiologically-diverse neurodegenerative diseases characterized by distinct pathological aggregates and affected brain regions. Development of effective treatments for dementia requires a better understanding of the common molecular and cellular defects in neurons that degenerate in response to misfolded protein accumulation. Using the powerful and versatile genetic model, Drosophila, we recently discovered that diverse aggregation-prone proteins trigger progressive neuropathology and shortened lifespan due to persistent activation of ER Ca2+ release. Here, we investigate the transcriptional programs underlying these changes in Ca2+ homeostasis. Our preliminary findings show that knockdown of metal regulatory transcription factor-1 (MTF- 1), an evolutionarily-conserved orchestrator of heavy metal homeostasis, suppressed the mortality in flies expressing various neurodegeneration-causing transgenes. Using a computational strategy, we identified the putative MTF-1 transcriptional targets in the fly genome, which were significantly upregulated in fly models of tauopathies, Alzheimer’s disease (AD), and Lewy Body dementia (LBD). These findings prompt our central hypothesis that MTF-1 contributes to the phenotypes observed in multiple fly models of neurodegeneration, and that attenuating MTF-1 activity would confer resilience to neuropathology stemming from the accumulation of misfolded proteins. To test this hypothesis, aim 1 seeks to determine whether aberrant MTF-1 activation is necessary and sufficient for driving degeneration in fly models of AD, tauopathies and LBD. Successful completion of this aim would identify pathways downstream of MTF-1 that underlie neuronal susceptibility to aggregation-prone proteins. In aim 2, we will identify the upstream mechanisms by which aggregation-prone proteins induce MTF-1-dependent neurotoxicity. The proposed research is relevant to human health as metal dyshomeostasis is implicated in AD and other dementias. By bringing to bear advanced genetic tools, flies offer a rapid and efficient platform for foundational studies aimed at uncovering the mechanisms of MTF-1-mediated neuropathology. This project lays the groundwork for future experiments in mouse models and iPSC-derived human neurons to determine whether targeting MTF-1 activity can impart resilience to dementia.