Pridopidine reduces mutant huntingtin-induced endoplasmic reticulum stress by modulation of the Sigma-1 receptor

J Neurochem. 2021 Jul;158(2):467-481. doi: 10.1111/jnc.15366. Epub 2021 Apr 28.


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.

Keywords: Huntington disease; Sigma-1 receptor; endoplasmic reticulum (ER) stress; neurodegeneration; unfolded protein response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • CRISPR-Cas Systems
  • Endoplasmic Reticulum Chaperone BiP
  • Endoplasmic Reticulum Stress / drug effects*
  • Gene Knockout Techniques
  • HEK293 Cells
  • Heat-Shock Proteins
  • Humans
  • Huntingtin Protein / genetics*
  • Huntingtin Protein / toxicity*
  • Mice
  • Mitochondrial Membranes / drug effects
  • Piperidines / pharmacology*
  • Receptors, sigma / drug effects*
  • Unfolded Protein Response / drug effects


  • Endoplasmic Reticulum Chaperone BiP
  • HTT protein, human
  • Heat-Shock Proteins
  • Huntingtin Protein
  • Piperidines
  • Receptors, sigma
  • sigma-1 receptor
  • pridopidine