Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8686372 | Neurobiology of Disease | 2018 | 45 Pages |
Abstract
Here we report a gain in function for mutant (mt) superoxide dismutase I (SOD1), a cause of familial amyotrophic lateral sclerosis (FALS), wherein small soluble oligomers of mtSOD1 acquire a membrane toxicity. Phosphatidylglycerol (PG) lipid domains are selectively targeted, which could result in membrane damage or “toxic channels” becoming active in the bilayer. This PG-selective SOD1-mediated membrane toxicity is largely reversible in vitro by a widely-available FDA-approved surfactant and membrane-stabilizer P188. Treatment of G93ASOD1 transgenic mice with P188 significantly delayed symptoms onset, extended survival and decreased motoneuron death. The use of P188 or an analogue, which targets mtSOD1 misfolding-induced membrane toxicity, may provide a new direction for ALS treatment.
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Authors
Jacob J. Riehm, Lijun Wang, Ghanashyam Ghadge, Michael Teng, Ana M. Correa, Jeremy D. Marks, Raymond P. Roos, Michael J. Allen,