I13 Pridopidine restores mitochondrial function and decreases er stress which is mediated through the S1R

Abstract

<h3>Background</h3> Pridopidine is a highly selective, potent Sigma-1 receptor (S1R) agonist in clinical development for HD and ALS. The S1R is a protein enriched at the endoplasmic reticulum (ER)-mitochondria interface and vital to multiple cellular mechanisms, including mitochondrial function and the ER stress response. By activating the S1R, pridopidine exerts neuroprotective effects in many models of neurodegenerative diseases, including HD. In HD neurons, abnormal ER and mitochondria function increase susceptibility to oxidative stress, causing cell death. <h3>Aims</h3> Assess the effects of pridopidine on mitochondrial function and ER stress in HD models. <h3>Methods</h3> In neurons from YAC128 HD model mice, mitochondria and ER structure were assessed., Mitochondrial function was assessed by measuring respiration, ATP production, membrane potential and reactive oxygen species. Motor and mitochondrial function was assessed in vivo in YAC128 mice. ER stress was assessed by measuring levels of proteins involved in the stress response in HEK293 cells expressing normal or mutant Htt. <h3>Results</h3> Pridopidine restores mitochondrial and ER structure and connectivity (p &lt; 0.0001), improves mitochondrial function, and rescues the cellular response to oxidative stress (p &lt; 0.01). The protective effect of pridopidine is confirmed in-vivo in YAC128 mice. Pridopidine-treated mice show restoration of mitochondrial function (p &lt; 0.05) and delayed motor symptom onset (p = 0.03). Pridopidine reduces levels of phosphorylated protein eIF2α (p &lt; 0.01), a marker for increased ER stress elevated by mutant Htt, as well as downstream ER stress markers CHOP (p &lt; 0.05), and GADD34 (p &lt; 0.01). The protective effects of pridopidine are abolished by deletion or inhibition of the S1R. <h3>Conclusion</h3> The protective effects of pridopidine are facilitated by S1R-mediated rescue of mitochondrial function and ER stress pathway, both disrupted in HD. These findings shed new light on pridopidine’s mechanism of action.