Advisory Committee Chair
Michael A Miller
Advisory Committee Members
Bradley Yoder
Chenbei Chang
Dale Dickinson
Etty Benveniste
Document Type
Dissertation
Date of Award
2012
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
In C. elegans, the major sperm protein (MSP) is the most abundant protein in sperm and functions as an intracellular cytoskeleton protein and a secreted extracellular signal that induces oocyte maturation and sheath contraction. Evolutionarily, MSP domain-containing proteins originate from the VAPs (VAMP/synaptobrevin-associated proteins), which comprise a highly conserved protein family with an MSP domain at the N-terminus and a transmembrane domain at the C-terminus. I have been studying the signaling role of VAP MSP domains using the C. elegans model system. In collaboration with Hugo Bellen's lab at Baylor College of Medicine, we have shown that C. elegans, Drosophila, and human VAP MSP domains are cleaved away from the transmembrane domain and secreted into the extracellular environment, where they act as ligands for Eph, Roundabout, and Lar-like receptors. A P56S missense mutation in the human VAPB MSP domain causes familial forms of amyotrophic lateral sclerosis (ALS) or spinal muscular atrophy (SMA), two neuromuscular diseases characterized by progressive motor neuron degeneration and loss of muscle function. We have shown that the P56S mutation prevents secretion of the VAP MSP domain, suggesting that VAPB MSP signaling plays a role in ALS pathogenesis. We also show that the C. elegans VAP homolog, VPR-1, functions as an extracellular signal secreted from neurons to control muscle energy homeostasis. VPR-1 triggers actin cytoskeletal rearrangements that in turn localizes mitochondria to myofilaments and promotes mitochondrial functions. Disruption of this signaling mechanism causes elevated DAF-16/FOXO transcription factor activity, which alters fat metabolism, ATP levels, and lifespan. My results may provide insight into the molecular mechanisms behind ALS and SMA.
Recommended Citation
Han, Sung Min, "The Role Of Vpr-1 Msp Signaling In C. Elegans" (2012). All ETDs from UAB. 1857.
https://digitalcommons.library.uab.edu/etd-collection/1857