Pridopidine protects neurons from mutant-huntingtin toxicity via the sigma-1 receptor

NEUROBIOLOGY OF DISEASE

卷:129

Article

Eddings, Chelsy R.¹  Arbez, Nicolas¹  Akimov, Sergey¹  Geva, Michal⁵  Hayden, Michael R.^5,6  Ross, Christopher A.^1,2,3,4 

[1] Johns Hopkins Univ, Sch Med, Dept Psychiat, Div Neurobiol, Baltimore, MD 21287 USA

[2] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA

[3] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21287 USA

[4] Johns Hopkins Univ, Sch Med, Dept Pharmacol, Baltimore, MD 21287 USA

[5] Prilenia Therapeut Dev LTD, Herzliyya, Israel

[6] Univ British Columbia, BC Childrens Hosp Res Inst, Ctr Mol Med & Therapeut, Vancouver, BC, Canada

关键词: Neuroprotection;    Huntingtin toxicity;    Huntington's disease;    Mutant-huntingtin;    Pridopidine;    3PPP;    Sigma-1 receptor;    Primary neurons;    Patient-derived induced pluripotent stem cells;   

DOI  :  10.1016/j.nbd.2019.05.009

来源: Elsevier

【 摘 要 】

Huntington's disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin gene (HTT), translated into a Huntingtin protein with a polyglutamine expansion. There is preferential loss of medium spiny neurons within the striatum and cortical pyramidal neurons. Pridopidine is a small molecule showing therapeutic potential in HD preclinical and clinical studies. Pridopidine has nanomolar affinity to the sigma-1 receptor (sigma-1R), which is located predominantly at the endoplasmic reticulum (ER) and mitochondrial associated ER membrane, and activates neuroprotective pathways. Here we evaluate the neuroprotective effects of pridopidine against mutant Huntingtin toxicity in mouse and human derived in vitro cell models. We also investigate the involvement of the sigma-1 receptor in the mechanism of pridopidine. Pridopidine protects mutant Huntingtin transfected mouse primary striatal and cortical neurons, with an EC50 in the mid nanomolar range, as well as HD patient-derived induced pluripotent stem cells (iPSCs). This protection by pridopidine is blocked by NE-100, a purported sigma-1 receptor antagonist, and not blocked by ANA-12, a reported TrkB receptor antagonist. 3PPP, a documented sigma-1 receptor agonist, shows similar neuroprotective effects. Genetic knock out of the sigma-1 receptor dramatically decreases protection from pridopidine and 3PPP, but not protection via brain derived neurotrophic factor (BDNF). The neuroprotection afforded by pridopidine in our HD cell models is robust and sigma-1 receptor dependent. These studies support the further development of pridopidine, and other sigma-1 receptor agonists as neuroprotective agents for HD and perhaps for other disorders.

【 授权许可】

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