title: Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal, progressive paralysis arising from the premature death of motor neurons. An inherited form is caused by a dominant mutation in the ubiquitously expressed superoxide dismutase (SOD1). SOD1 mutant expression within motor neurons is a determinant of onset and early disease, and mutant accumulation within microglia accelerates disease progression. Muscle also is a likely primary source for toxicity, because retraction of motor axons from synaptic connections to muscle is among the earliest presymptomatic events. To test involvement of muscle in ALS, viral delivery of transcription-mediated siRNA is shown to suppress mutant SOD1 accumulation within muscle alone but to be insufficient to maintain grip strength, whereas delivery to both motor neurons and muscle is sufficient. Use of a deletable mutant gene to diminish mutant SOD1 from muscle did not affect onset or survival. Finally, follistatin expression encoded by adeno-associated virus chronically inhibited myostatin and produced sustained increases in muscle mass, myofiber number, and fiber diameter, but these increases did not affect survival. Thus, SOD1-mutant-mediated damage within muscles is not a significant contributor to non-cell-autonomous pathogenesis in ALS, and enhancing muscle mass and strength provides no benefit in slowing disease onset or progression.
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Miller
authors.forename: Soo H
authors.initials: SH
authors.lastname: Kim
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanaka
authors.forename: Mark
authors.initials: M
authors.lastname: Hester
authors.forename: Priya
authors.initials: P
authors.lastname: Umapathi
authors.forename: Hannah
authors.initials: H
authors.lastname: Arnson
authors.forename: Liza
authors.initials: L
authors.lastname: Rizo
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Mendell
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kaspar
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D000229:Dependovirus / Q000378:metabolism; D018450:Disease Progression; D038681:Follistatin / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics; D018737:Hand Strength / Q000502:physiology; D006801:Humans; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D038681:Follistatin; D034741:RNA, Small Interfering; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1