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J Clin Invest. 2020 Feb 10. pii: 131989. doi: 10.1172/JCI131989. [Epub ahead of print]

Muscle-specific SMN reduction reveals motor neuron-independent disease in spinal muscular atrophy models.

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Department of Pathology & Cell Biology, and.
Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, New York, USA.
Department of Biological Sciences, University of Southern California, Los Angeles, California, USA.
Department of Neurology, and.
Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York, USA.


Paucity of the survival motor neuron (SMN) protein triggers the oft-fatal infantile-onset motor neuron disorder, spinal muscular atrophy (SMA). Augmenting the protein is one means of treating SMA and recently led to FDA approval of an intrathecally delivered SMN-enhancing oligonucleotide currently in use. Notwithstanding the advent of this and other therapies for SMA, it is unclear whether the paralysis associated with the disease derives solely from dysfunctional motor neurons that may be efficiently targeted by restricted delivery of SMN-enhancing agents to the nervous system, or stems from broader defects of the motor unit, arguing for systemic SMN repletion. We investigated the disease-contributing effects of low SMN in one relevant peripheral organ - skeletal muscle - by selectively depleting the protein in only this tissue. We found that muscle deprived of SMN was profoundly damaged. Although a disease phenotype was not immediately obvious, persistent low levels of the protein eventually resulted in muscle fiber defects, neuromuscular junction abnormalities, compromised motor performance, and premature death. Importantly, restoring SMN after the onset of muscle pathology reversed disease. Our results provide the most compelling evidence yet for a direct contributing role of muscle in SMA and argue that an optimal therapy for the disease must be designed to treat this aspect of the dysfunctional motor unit.


Neuromuscular disease; Neuroscience

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