S1R knockout data indicate that basal S1R activity may be important for mitigating oxidative stress and regulating the actin cytoskeleton via Rac-GTP signaling (Tsai et al., 2009), whereas the agonist-mediated rescue of HD MSN spines or AD mushroom spines may involve normalization of calcium signaling (Wu et al., 2016, 2018; Ryskamp et al., 2017, 2019). This evidence concerns the gene TMBIM4 and Alzheimer disease.