Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis

Timothy M. Miller, Soo H. Kim, Koji Yamanaka, Mark Hester, Priya Umapathi, Hannah Arnson, Liza Rizo, Jerry R. Mendell, Fred H. Gage, Don W. Cleveland, Brian K. Kaspar

Research output: Contribution to journalArticle

126 Scopus citations

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.

Original languageEnglish
Pages (from-to)19546-19551
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number51
DOIs
StatePublished - Dec 19 2006
Externally publishedYes

Keywords

  • Adeno-associated virus
  • G93A SOD1
  • Motor neuron
  • Myostatin
  • siRNA

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