title: Voluntary Running Triggers VGF-Mediated Oligodendrogenesis to Prolong the Lifespan of Snf2h-Null Ataxic Mice.
abstract: Exercise has been argued to enhance cognitive function and slow progressive neurodegenerative disease. Although 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 impairs cerebellar development producing mice with poor motor function, progressive ataxia, and death between postnatal days 25-45. Here, we show that voluntary running induced an endogenous brain repair mechanism that resulted in a striking increase in hindbrain 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 promote oligodendrogenesis in vitro, whereas Snf2h cKO mice treated with full-length VGF-encoding adenoviruses removed the requirement of exercise for survival. Together, these results suggest that VGF delivery could represent a therapeutic strategy for cerebellar ataxia and other pathologies of the CNS.
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L1, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, ON K1N 6N5, Canada; Center for Biomedical Research, Faculty of Biological Sciences, Universidad Andres Bello, Avenida República 239, Santiago, Chile. Electronic address: matias.alvarez-saavedra@nyumc.org.
authors.forename: Matías
authors.initials: M
authors.lastname: Alvarez-Saavedra
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L1, Canada.
authors.forename: Yves
authors.initials: Y
authors.lastname: De Repentigny
authors.affiliation: Department of Biochemistry, Microbiology & Immunology, University of Ottawa, ON K1N 6N5, Canada; Ottawa Institute of Systems Biology (OISB), University of Ottawa, ON K1N 6N5, Canada.
authors.forename: Doo
authors.initials: D
authors.lastname: Yang
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L1, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, ON K1N 6N5, Canada.
authors.forename: Ryan W
authors.initials: RW
authors.lastname: O'Meara
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L1, Canada.
authors.forename: Keqin
authors.initials: K
authors.lastname: Yan
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L1, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, ON K1N 6N5, Canada.
authors.forename: Lukas E
authors.initials: LE
authors.lastname: Hashem
authors.affiliation: Department of Biochemistry, Microbiology & Immunology, University of Ottawa, ON K1N 6N5, Canada; Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1N 6N5, Canada.
authors.forename: Lemuel
authors.initials: L
authors.lastname: Racacho
authors.affiliation: Department of Biochemistry, Microbiology & Immunology, University of Ottawa, ON K1N 6N5, Canada; Ottawa Institute of Systems Biology (OISB), University of Ottawa, ON K1N 6N5, Canada.
authors.forename: Ilya
authors.initials: I
authors.lastname: Ioshikhes
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1N 6N5, Canada; Department of Pediatrics, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Bulman
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L1, Canada; Department of Biochemistry, Microbiology & Immunology, University of Ottawa, ON K1N 6N5, Canada.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Parks
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L1, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, ON K1N 6N5, Canada.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kothary
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L1, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, ON K1N 6N5, Canada; Department of Biochemistry, Microbiology & Immunology, University of Ottawa, ON K1N 6N5, Canada. Electronic address: dpicketts@ohri.ca.
authors.forename: David J
authors.initials: DJ
authors.lastname: Picketts
mesh_terms: D000251:Adenosine Triphosphatases / Q000172:deficiency* / Q000378:metabolism; D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D001259:Ataxia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency* / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D008136:Longevity; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D009186:Myelin Sheath / Q000378:metabolism; D055495:Neurogenesis; D009479:Neuropeptides / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D010805:Physical Conditioning, Animal; D012249:Rhombencephalon / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D017423:Sequence Analysis, RNA; D015398:Signal Transduction
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D009479:Neuropeptides; C522413:VGF peptide; D000251:Adenosine Triphosphatases; C498725:Smarca5 protein, mouse
keywords: Purkinje; Smarca5; Snf2h; VGF; cerebellum; exercise; myelin; oligodendrocyte; remyelination; running