Mutations in sigma-1 receptor (σ₁R) gene are found in ALS. The σ₁R forms oligomers that are regulated by its ligands. However, little is known about the effect of mutations. Here, we transfected motor neuronal NSC-34 cells with σ₁R-mCherry (mCh), σ₁R^E102Q-mCh or untagged forms to assess detergent solubility and subcellular distribution by immunostaining and FRAP. The oligomeric state was assessed using crosslinker. Wildtype σ₁Rs were soluble to detergents, but the mutants were enriched in the insoluble fraction. In the soluble fraction, distribution of mutants appeared in higher sucrose density fractions. Mutants formed aggregates that were co-stained with p62, ubiquitin, and p-PERK, and which had lower recovery in FRAP. Acute treatment with σ₁R agonist SA4503 failed to improve recovery, prolonged treatment (48 h) reduced σ₁R^E102Q-mCh insolubility and inhibited apoptosis. While σ₁R-mCh formed monomers/dimers, σ₁R^E102Q-mCh also formed trimers/tetramers. SA4503 reduced the four types in the insoluble fraction but elevated monomers in the soluble fraction. Co-expression of σ₁R-mCh reduced σ₁R^E102Q insolubility. These results suggest that the agonist and wildtype σ₁R can modify the detergent insolubility, toxicity, and oligomeric states of σ₁R^E102Q. Pharmacological and genetic approaches may be promising to treat σ₁R-related ALS.