Neuronal overexpression of human VAPB slows motor impairment and neuromuscular denervation in a mouse model of ALS

Hum Mol Genet. 2016 Nov 1;25(21):4661-4673. doi: 10.1093/hmg/ddw294.


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 lifespan, even in this highly aggressive model of disease. Our findings lend support for a protective role of VAPB in neuromuscular health.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Denervation
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Neuron Disease / genetics
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Mutation
  • Neuromuscular Diseases / genetics
  • Neuromuscular Diseases / metabolism*
  • Neurons / metabolism
  • Spinal Cord / metabolism
  • Superoxide Dismutase-1 / genetics
  • Vesicular Transport Proteins / biosynthesis*
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism


  • VAPB protein, human
  • Vesicular Transport Proteins
  • Superoxide Dismutase-1