Pridopidine reduces mutant huntingtin‐induced endoplasmic reticulum stress by modulation of the Sigma‐1 receptor. Issue 2 (28th April 2021)

• Record Type: Journal Article
• Authors: Shenkman, Marina; Geva, Michal; Gershoni‐Emek, Noga; Hayden, Michael R.; Lederkremer, Gerardo Z.
• Is Part Of: Journal of neurochemistry. Volume 158:Issue 2(2021)
• Page Start: 467
• Page End: 481
• Publication Date: 2021-04-28
• Subjects: endoplasmic reticulum (ER) stress -- Huntington disease -- neurodegeneration -- Sigma‐1 receptor -- unfolded protein response; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15366
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: The endoplasmic reticulum (ER)‐localized Sigma‐1 receptor (S1R) is neuroprotective in models of neurodegenerative diseases, among them Huntington disease (HD). Recent clinical trials in HD patients and preclinical studies in cellular and mouse HD models suggest a therapeutic potential for the high‐affinity S1R agonist pridopidine. However, the molecular mechanisms of the cytoprotective effect are unclear. We have previously reported strong induction of ER stress by toxic mutant huntingtin (mHtt) oligomers, which is reduced upon sequestration of these mHtt oligomers into large aggregates. Here, we show that pridopidine significantly ameliorates mHtt‐induced ER stress in cellular HD models, starting at low nanomolar concentrations. Pridopidine reduced the levels of markers of the three branches of the unfolded protein response (UPR), showing the strongest effects on the PKR‐like endoplasmic reticulum kinase (PERK) branch. The effect is S1R‐dependent, as it is abolished in cells expressing mHtt in which the S1R was deleted using CRISPR/Cas9 technology. mHtt increased the level of the detergent‐insoluble fraction of S1R, suggesting a compensatory cellular mechanism that responds to increased ER stress. Pridopidine further enhanced the levels of insoluble S1R, suggesting the stabilization of activated S1R oligomers. These S1R oligomeric species appeared in ER‐localized patches, and not in the mitochondria‐associated membranes nor the ER‐derived quality control compartment. The colocalization of S1R with the chaperone BiP was significantly reduced by mHtt, and pridopidine restored this colocalization to normal, unstressed levels. Pridopidine increased toxic oligomeric mHtt recruitment into less toxic large sodium dodecyl sulfate‐insoluble aggregates, suggesting that this in turn reduces ER stress and cytotoxicity. Abstract : The high‐affinity Sigma‐1 receptor (S1R) agonist pridopidine is neuroprotective in models of Huntington disease. Here we show that pridopidine reduces mutant huntingtin (mHtt) ‐induced endoplasmic reticulum (ER) stress by increasing activated S1R oligomeric species and promoting toxic mHtt recruitment into less toxic large detergent‐insoluble aggregates. S1R activation involves Binding immunoglobulin protein (BiP) displacement by misfolded proteins and leads to Ca 2+ transport modulation through the Inositol trisphosphate receptor (IP3R). Similar mechanisms may operate in S1R‐dependent neuroprotective effects in other neurodegenerative diseases.