Running triggers VGF-mediated oligodendrogenesis to prolong the lifespan of Snf2h-null ataxic mice.. Mus musculus strain:C57BL/6

Exercise enhances cognitive function and slows progressive neurodegenerative disease. While exercise promotes neurogenesis, oligodendrogenesis and adaptive myelination are also significant contributors to brain repair and brain health. Nonetheless, the molecular details underlying these effects remain poorly understood. Conditional ablation of the Snf2h gene (Snf2h cKO) impairs cerebellar development producing mice with poor motor function, progressive ataxia and death. Here we show that voluntary running induced an endogenous brain repair mechanism that resulted in a striking increase in cerebellar myelination and the long-term survival of Snf2h cKO mice. Further experiments identified the VGF growth factor as a major driver underlying this effect. VGF neuropeptides could promote oligodendrogenesis in vitro, while Snf2h cKO mice treated with VGF-encoding adenoviruses obliterated the requirement of exercise for survival. Together, these results suggest that VGF neuropeptide delivery could represent a therapeutic strategy for cerebellar ataxia and other pathologies of the central nervous system.