Poloxamer 188 decreases membrane toxicity of mutant SOD1 and ameliorates pathology observed in SOD1 mouse model for ALS

NEUROBIOLOGY OF DISEASE

卷:115

Article

Riehm, Jacob J.^1,5  Wang, Lijun^2,6  Ghadge, Ghanashyam²  Teng, Michael^1,7  Correa, Ana M.³  Marks, Jeremy D.⁴  Roos, Raymond P.²  Allen, Michael J.^1,8 

[1] Univ Chicago, Dept Med, Sect Pulm Crit Care, 5841 S Maryland Ave, Chicago, IL 60637 USA

[2] Univ Chicago, Dept Neurol, 5841 S Maryland Ave, Chicago, IL 60637 USA

[3] Univ Chicago, Dept Biochem & Mol Biol, 920 E 58Th St, Chicago, IL 60637 USA

[4] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA

[5] AbbVie Inc, Oncol Discovery, 1 North Waukegan Rd, N Chicago, IL 60064 USA

[6] BloodCtr Wisconsin, 638 N 18th St, Milwaukee, WI 53233 USA

[7] Castle Global, 255 Calif Ave,Suite 800, San Francisco, CA 94130 USA

[8] Biometrology, 1448 E 52nd St, Chicago, IL 60615 USA

关键词: ALS;    P188;    F68;    Poloxamer;    Protein misfolding;    Superoxide dismutase;    SOD1;    G93A;    Atomic force microscopy;    AFM;    Electrophysiology;    Membrane toxicity;    Lipid peroxidation;   

DOI  :  10.1016/j.nbd.2018.03.014

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

Free