All ETDs from UAB

Advisory Committee Chair

Michael A Miller

Advisory Committee Members

Chenbei Chang

Jim Collawn

Robin Lorenz

Jianbo Wang

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


In humans, a P56S point mutation in the VAPB/ALS8 MSP domain is associated with amyotrophic lateral sclerosis (ALS) and late-onset spinal muscular atrophy (SMA). The N-terminal MSP domain is cleaved from the C-terminus, and secreted through an unknown, nonconventional manner. The P56S mutation inhibits secretion of the MSP domain. We use Caenorhabditis elegans to study live secretion of VPR-1, as well as to understand vMSP receptor signaling in muscle and gonad. To study the secretion mechanism of VPR-1 we created a transgenic line of C. elegans with a fluorescently tagged VPR-1. Using this model, we were able to visualize live secretion of N-terminal VPR-1 from neurons. We also observed trafficking of N-terminal VPR-1 along axons. We validated that the fluorescent tags did not drastically alter VPR-1 MSP cleavage through a Western Blot which showed predicted protein bands for the full length fluorescent protein, as well as the cleavage product. This model provided the first insight into live secretion of VPR-1. We explored the complexing behavior of the three identified vMSP receprots: VAB-1, CLR-1, and ROBO/SAX-3. We found evidence suggesting that VAB-1 and SAX-3 as well as CLR-1 and SAX-3 form heteromeric complexes. vMSP presence appears to increase complexing behavior between CLR-1 and SAX-3. We further investigated vMSP signaling with CLR-1 in muscle and gonad development of C. elegans. We found that vMSP signaling in the gonad is independent of the CLR-1 receptor, and that CLR-1 signaling plays no obvious role in gonad development. We found that vMSP and CLR-1 signaling is important in localizing mitochondria to the I-bands in muscle during the L4/adult stage, and that CLR-1 has an important, and perhaps vMSP independent, signaling role early in muscle development. We also show that endogenous CLR-1 expression is in the somatic gonad and muscle plasma membrane, and expression is independent of vMSP signaling. A suppressor screen identified survival motor neuron 1 (smn-1) as a suppressor of VPR-1 muscle mitochondria defects. We found that smn-1 and arx-2, another identified suppressor of VPR-1 muscle mitochondria defects, colocalize at muscle myofilaments. Overexpression of ARX-2 partially rescues mitochondria defects associated with SMN-1 loss. This presents a possible link between the P56S mutation and ALS and SMA.



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