Exercise mimetic induces coordination of multiple neuroprotective mechanisms with potential application to multiple diseases
Audrey S. Dickey1*, Grace Sahyouni1, Albert La Spada1
1Duke University, Neurology Dept.
*corresponding author: Audrey.Dickey@Duke.edu
From years of research in the neurodegenerative field, both shared and disease-specific mechanisms have been uncovered.
Previous work from us and others indicated that an exercise mimetic can ameliorate neuropathology and motor symptoms in models of Huntington disease: patient iPSC-derived neurons and HD N171-82Q mice (Dickey, et al., 2016. NMED), models of Parkinson Disease, and models of Alzheimer disease: APP/PS1 mice (Casali, et al, 2018. J.Neuroinflam). Neuroprotective mechanisms so far elucidated include inducing oxidative phosphorylation, reducing mitochondria fragmentation, and promoting autophagy to address aggregates (Dickey, et al., 2017. STM).
Our RNA-SEQ & ChIP-SEQ results indicate that this exercise mimetic/transcriptional regulator activates more neuroprotective mechanisms than previously thought, potentially applying to multiple diseases.
In addition to the mechanisms above, this exercise mimetic reduces ROS, represses ER-mediated stress, calms inflammation, prevents excitotoxicity, and diminishes propagation of toxic material. These findings were derived from studies utilizing mice, primary neuron cultures, and cell lines.
We have also been investigating the mechanism through which this mimetic is able to coordinate these multiple downstream effects. Our follow-up studies indicate that the transcriptional coordinator is able to act via diverse mechanisms.