<p>Pridopidine is a selective sigma-1 receptor (S1R) agonist in clinical development for Huntington’s Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). Activation of the S1R by pridopidine is neuroprotective in multiple preclinical models of neurodegenerative disease. The sigma-2 receptor (S2R) is evolutionarily and structurally unique from the S1R. Nevertheless, the S1R and S2R share an overlapping yet distinct ligand binding profile. Inhibition of the S2R is neuroprotective and S2R antagonists are in clinical development for Alzheimer’s Disease (AD), ⍺-synucleinopathies, and dry age-related macular degeneration. In this study, we hypothesized that simultaneous activation of the S1R by pridopidine and inhibition of the S2R by the selective S2R antagonist FA10 might provide enhanced protection against mutant huntingtin (mHTT) expression in an in vitro model of neurodegeneration. Consistent with previous studies, pridopidine reduced neuronal cell death in a mouse primary neuron mHTT model. Similarly, we found that inhibition of the S2R by FA10 was also sufficient to protect against mHTT induced neurodegeneration in this model. The combination treatment of pridopidine and FA10 achieved greater efficacy than either compound alone, even at lower concentrations. The combination of these compounds may allow for lower efficacious doses leading to improved safety profiles and reduced off-target effects. This novel combinatorial approach, in which the S1R is activated while simultaneously inhibiting the S2R may prove to be a highly effective therapeutic strategy for HD and other neurodegenerative diseases.</p>