Journal
HUMAN MOLECULAR GENETICS
Volume 25, Issue 21, Pages 4661-4673Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddw294
Keywords
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Funding
- Robert A. and Rene E. Belfer Family Foundation
- BrightFocus Foundation [A2010097]
- National Institutes of Health [R21 AG038856]
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Four mutations in the VAMP/synaptobrevin-associated protein B (VAPB) gene have been linked to amyotrophic lateral sclerosis (ALS) type 8. The mechanism by which VAPB mutations cause motor neuron disease is unclear, but studies of the most common P56S variant suggest both loss of function and dominant-negative sequestration of wild-type protein. Diminished levels of VAPB and its proteolytic cleavage fragment have also been reported in sporadic ALS cases, suggesting that VAPB loss of function may be a common mechanism of disease. Here, we tested whether neuronal overexpression of wild-type human VAPB would attenuate disease in a mouse model of familial ALS1. We used neonatal intraventricular viral injections to express VAPB or YFP throughout the brain and spinal cord of superoxide dismutase (SOD1) G93A transgenic mice. Lifelong elevation of neuronal VAPB slowed the decline of neurological impairment, delayed denervation of hindlimb muscles, and prolonged survival of spinal motor neurons. Collectively, these changes produced a slight but significant extension in life-span, even in this highly aggressive model of disease. Our findings lend support for a protective role of VAPB in neuromuscular health.
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