Editors' ChoiceAmyotrophic Lateral Sclerosis

Slowing Motor Neuron Degeneration, Naturally

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Science Translational Medicine  28 Oct 2009:
Vol. 1, Issue 4, pp. 4ec13
DOI: 10.1126/scitranslmed.3000514

Motor neurons can be exceedingly long, extending their axons from brain to spinal cord and from spinal cord all the way down our arms and legs. When they degenerate, as they do in amyotrophic lateral sclerosis (or ALS), muscle control is lost and muscle tissue eventually atrophies. ALS has no cure, so scientists and patients alike will welcome the recent report by Zhong et al., which shows that a natural blood component called activated protein C (APC) can slow progression of the disease in mice carrying a human, ALS-causing mutation in the superoxide dismutase–1 gene (SOD-1). This mutation underlies ALS in about 2% of patients, not by disruption of the protein’s enzymatic activity, but by poorly understood toxic effects of the mutated protein in neurons and the surrounding glial cells. When APC is given to mice with mutant SOD-1, it crosses the blood-brain barrier via an active transporter, binds to neurons and glia, where it triggers a signaling pathway through the transcription factor Sp1, and inhibits SOD-1 mRNA production. With the resulting decline in mutant SOD-1 protein concentrations in cells, the mice remain mobile longer, relative to control animals. The transfer of ALS therapies from mice to humans has been problematic, but APC has two advantages: It has already been FDA approved for use in adults and it crosses the blood-brain barrier. This latter advantage allows simple systemic administration of APC, which can then reach motor neurons wherever they are in the body.

Z. Zhong et al., Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells. J. Clin. Invest. 19 October 2009 (10.1172/JCI38476) [Full Text]

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