Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

Dysregulation of cyclin-dependent kinase 5 (cdk5) per relative concentrations of its activators p35 and p25 is implicated in neurodegenerative diseases. P35 has a short t ½ and undergoes rapid proteasomal degradation in its membrane-bound myristoylated form. P35 is converted by calpain to p25, which, along with an extended t ½, promotes aberrant activation of cdk5 and causes abnormal hyperphosphorylation of tau, thus leading to the formation of neurofibrillary tangles. The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperone that is implicated in neuronal survival. However, the specific role of the Sig-1R in neurodegeneration is unclear. Here we found that Sig-1Rs regulate proper tau phosphorylation and axon extension by promoting p35 turnover through the receptor’s interaction with myristic acid. In Sig-1R–KO neurons, a greater accumulation of p35 is seen, which results from neither elevated transcription of p35 nor disrupted calpain activity, but rather to the slower degradation of p35. In contrast, Sig-1R overexpression causes a decrease of p35. Sig-1R–KO neurons exhibit shorter axons with lower densities. Myristic acid is found here to bind Sig-1R as an agonist that causes the dissociation of Sig-1R from its cognate partner binding immunoglobulin protein. Remarkably, treatment of Sig-1R–KO neurons with exogenous myristic acid mitigates p35 accumulation, diminishes tau phosphorylation, and restores axon elongation. Our results define the involvement of Sig-1Rs in neurodegeneration and provide a mechanistic explanation that Sig-1Rs help maintain proper tau phosphorylation by potentially carrying and providing myristic acid to p35 for enhanced p35 degradation to circumvent the formation of overreactive cdk5/p25. Significance Neurodegeneration is tightly linked to tauopathy as a result of the overactivated cyclin-dependent kinase (cdk) 5 in the form of cdk5/p25. P35, another activator of cdk5, which is short-lived and myristoylated, is cleaved by calpain to the degradation-resistant activator p25. One way to tune down the aberrant, overreactive cdk/p25 is to reduce available p35. The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum (ER) chaperone of unknown relation to tauopathy. Here we found that Sig-1Rs bind myristic acid and promote the degradation of p35. Further, the aberrant tau hyperphosphorylation and stunting of axon elongation in Sig-1R–KO neurons are mitigated by exogenously added myristic acid. Our results establish the role of