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Gene therapy demonstrates that muscle is not a primary target for non-cell autonomous toxicity in familial ALS

Kim, Soo Hyun
http://rave.ohiolink.edu/etdc/view?acc_num=osu1164829314

Abstract Details

2006, Doctor of Philosophy, Ohio State University, Biochemistry.
Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neuromuscular disease arising from premature death of motor neurons in the brainstem and spinal cord. Approximately 20% of familial cases of ALS are genetically linked to mutant Cu/Zn superoxide dismutase-1 (SOD1). While the hypothesis that gain of toxicity of mutant SOD1 may cause the disease is generally accepted, the ubiquitous expression of mutant SOD1 makes it hard to delineate its primary target. Previously, neither neuron specific expression nor astrocyte-specific expression provoked motor neuron degeneration. It suggested a non-cell autonomous toxicity, and the implication of multiple cell types in pathogenesis. Recent study showed that the toxicity of mutant SOD1 within motor neuron is crucial to onset and early phase of disease while mutant SOD1 within microglia accelerates disease progression. Given that deterioration of neuromuscular junction is one of earlier symptoms and the depletion or insufficient supply of various neurotrophic factors from degenerated muscle may initiate or promote motor neuron disease, mutant SOD1 damage within skeletal muscle is also a likely primary source for toxicity. This hypothesis was tested with gene therapeutic and genetic approaches. Even though viral delivered siRNA (short interfering RNA) against mutant SOD1 into various muscle groups significantly diminished mutant SOD1 expression exclusively in muscles, it was insufficient to maintain grip strength. In contrast, the reduction of mutant SOD1 both in motor neuron and muscle is sufficient to preserve motor function. The conditional deletion of mutant SOD1 from muscle did not affect onset or survival. Alternatively, a viral vector encoding Follistatin, a muscle enhancing gene, was administrated to delay disease progress by rescuing muscle atrophy. Follistatin produced sustained increase of whole muscle mass, but the motor function was transiently improved. Indeed, survival was not extended. Therefore, mutant SOD1 within muscle is not a primary contributor to non-cell autonomous pathogenesis of ALS, and the enhancement of muscle mass provides no benefits in slowing disease onset or progression.
K. Kaspar (Advisor)
P. Young (Other)
D. Oberdick (Other)
K. Clark (Other)
115 p.
Biology, Molecular
ALS; gene; therapy muscle

Recommended Citations

Citations

  • Kim, S. H. (2006). Gene therapy demonstrates that muscle is not a primary target for non-cell autonomous toxicity in familial ALS [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1164829314

    APA Style (7th edition)

  • Kim, Soo. Gene therapy demonstrates that muscle is not a primary target for non-cell autonomous toxicity in familial ALS. 2006. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1164829314.

    MLA Style (8th edition)

  • Kim, Soo. "Gene therapy demonstrates that muscle is not a primary target for non-cell autonomous toxicity in familial ALS." Doctoral dissertation, Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=osu1164829314

    Chicago Manual of Style (17th edition)

osu1164829314
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© 2006, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.