The overall objective of our work is to understand how nerve terminals and axons are maintained throughout
life and how they respond to injury. In the peripheral nervous system (PNS), long primary motor and sensory
axons and their terminals are susceptible to a wide variety of pro-degenerative insults, including metabolic stress
during diabetes, neurotoxicities of chemotherapy drugs, traumatic injuries, and genetic disorders including
Charcot-Marie-Tooth and Amyotrophic Lateral Sclerosis (ALS). In these disorders, terminals and axons are often
the first affected structures, and their degeneration precedes cell body death. By mapping out the cellular,
genetic, and biochemical landscape of the early events of nerve terminal and axon degeneration, we might
identify ways to delay or prevent this degeneration in neurodegenerative disorders.
We are focused on the axonal and synaptic functions of TMEM184b, a newly discovered 7-pass
transmembrane protein, in the PNS. Loss of TMEM184b in mice causes progressive dystrophies in both motor
and sensory nerve terminals, and also causes sensorimotor deficits. In addition to these nerve terminal
phenotypes, reduction of TMEM184b in Drosophila or in mice leads to prolonged axon integrity after injury,
suggesting TMEM184b is active in the axon degeneration cascade. Accumulations of autophagosomes and
lysosomes, compartments responsible for protein and organelle degradation, are seen in mutant tissues. Based
on these data, we hypothesize that TMEM184b regulates a step in autophagy. Because autophagy is known to
promote axon degeneration and also alter synapse structure, this hypothesis would explain both the axon and
synapse phenotypes of TMEM184b mutant mice.
Using both mouse and Drosophila systems, we will test our hypothesis with a combination of molecular and
genetic analysis, electrophysiology, cell biology, and behavior. In Aim 1, we will ascertain the root causes of the
sensorimotor deficits seen in both flies and mice lacking TMEM184b by investigating neuromuscular synaptic
transmission and sensory transduction, molecularly characterizing terminal dystrophies, and evaluating
peripheral nerve axon transport. In Aim 2, we will probe the cellular and molecular pathways controlled by
TMEM184b in cultured neurons and explanted tissues, with a particular focus on linking TMEM184b biological
activity to the control of autophagy. In Aim 3, we will identify how TMEM184b contributes to pro-degenerative
pathways in injured nerves using genetic epistasis and biochemistry, and we will ask whether TMEM184b's role
in axon degeneration is conserved in the central nervous system.
In summary, our research will describe a new mechanism of autophagy control in neurons that may underlie
early stages of neurodegenerative diseases. This work will contribute to the discovery of new strategies to block
nerve terminal and axon degeneration in neurodegenerative disorders.
