title: Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid.
abstract: 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 t½ and undergoes rapid proteasomal degradation in its membrane-bound myristoylated form. P35 is converted by calpain to p25, which, along with an extended t½, 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.
authors.affiliation: Cellular Pathobiology Section, Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, MD 21224 stsai@intra.nida.nih.gov tsu@intra.nida.nih.gov.
authors.forename: Shang-Yi A
authors.initials: SY
authors.lastname: Tsai
authors.affiliation: Cellular Pathobiology Section, Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, MD 21224.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pokrass
authors.affiliation: Cellular Pathobiology Section, Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, MD 21224.
authors.forename: Neal R
authors.initials: NR
authors.lastname: Klauer
authors.affiliation: Cellular Pathobiology Section, Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, MD 21224.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nohara
authors.affiliation: Cellular Pathobiology Section, Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, MD 21224 stsai@intra.nida.nih.gov tsu@intra.nida.nih.gov.
authors.forename: Tsung-Ping
authors.initials: TP
authors.lastname: Su
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure; D002154:Calpain / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D019814:Myristic Acid / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000502:physiology; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D017480:Receptors, sigma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D002154:Calpain; D051360:Cyclin-Dependent Kinase 5; D019814:Myristic Acid; D010770:Phosphotransferases; D046988:Proteasome Endopeptidase Complex; D017480:Receptors, sigma; D016875:tau Proteins; D000097605:Sigma-1 Receptor; C492236:Cdk5r1 protein, mouse; C558298:Mapt protein, mouse
keywords: axon growth; cdk5; myristic acid; p35; sigma-1 receptor