Sigma 2 receptor/TMEM97 as a potential therapeutic target for neurodegenerative disorders

Huntington’s disease (HD) is a devastating neurodegenerative disease resulting from a CAG/ polyglutamine expansion in Huntingtin (HTT), with no disease-modifying treatment. Current gene therapies targeting the mutant huntingtin (mHTT) have faced challenges, which have prompted continued interest in small molecules as potential therapeutic agents. We focused on a set of small molecules that selectively bind to sigma 2 receptor (σ2R), which was identified recently as the transmembrane protein 97 (σ2R/TMEM97) and located in the endoplasmic reticulum. Although the exact biological function of σ2R/TMEM97 is unclear, evidence indicated that σ2R/TMEM97 modulates cholesterol metabolism and lysosomal degradation and may be involved in ER stress regulation. Aim: to assess the potential of small molecules targeting σ2R/TMEM97 in reducing mHTT toxicity and to explore the role of σ2R/TMEM97 in HD pathogenesis. Methods: Using our primary neuronal HD cell model (involving transfection of mutant Htt), we tested σ2R/TMEM97 selectively binding ligands in control and KO neurons and conducted Co-IP experiments to explore the interaction between σ2R/TMEM97 and HTT/mHTT. Results: σ2R/TMEM97 selective modulators protected neurons from mHTT-induced toxicity. Knocking down TMEM97 conferred cell protection, while TMEM97 overexpression exacerbated cell toxicity induced by mHTT. TMEM97-/- primary neurons exhibited resilience to mHTT-induced toxicity. Co-IP experiments suggest that σ2R/TMEM97 interacts with HTT/mHTT. Conclusion: Small molecules selectively targeting σ2R/TMEM97 present a promising approach to HD treatment. Targeting σ2R/TMEM97 is a novel therapeutic mechanism to treat HD and related neurodegenerative diseases.