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

Shang-Yi A Tsai1, Michael J Pokrass2, Neal R Klauer2

  • 1Cellular 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.

Proceedings of the National Academy of Sciences of the United States of America
|May 13, 2015
PubMed

Insights

The sigma-1 receptor (Sig-1R) regulates tau phosphorylation by promoting p35 protein degradation. Myristic acid binding to Sig-1R enhances p35 turnover, mitigating neurodegenerative processes and restoring axon growth.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Dysregulation of cyclin-dependent kinase 5 (cdk5) activity, driven by altered p35/p25 ratios, is linked to neurodegenerative diseases.
  • The sigma-1 receptor (Sig-1R), an endoplasmic reticulum chaperone, is involved in neuronal survival, but its precise role in neurodegeneration remains unclear.
  • Aberrant tau hyperphosphorylation, leading to neurofibrillary tangles, is a hallmark of neurodegenerative conditions.

Purpose of the Study:

  • To elucidate the specific role of the sigma-1 receptor (Sig-1R) in regulating tau phosphorylation and neuronal morphology.
  • To investigate the mechanism by which Sig-1R influences the turnover of its activator p35.
  • To determine the therapeutic potential of modulating Sig-1R activity in the context of neurodegeneration.

Main Methods:

  • Utilized Sig-1R knockout (Sig-1R-KO) and overexpression neuronal models.
  • Assessed p35 protein levels, degradation rates, and tau phosphorylation.
  • Investigated the interaction between Sig-1R, myristic acid, and p35 using biochemical and cellular assays.
  • Examined axon extension and density in manipulated neuronal cultures.

Main Results:

  • Sig-1R deficiency led to increased p35 accumulation due to impaired degradation, not altered transcription or calpain activity.
  • Sig-1R-KO neurons exhibited reduced axon length and density, along with increased tau phosphorylation.
  • Myristic acid acts as an agonist for Sig-1R, promoting p35 degradation and subsequently reducing tau phosphorylation and restoring axon growth in Sig-1R-KO neurons.

Conclusions:

  • Sig-1Rs are crucial for maintaining proper tau phosphorylation and axon integrity by facilitating p35 turnover.
  • The interaction of myristic acid with Sig-1R is key to enhancing p35 degradation, offering a potential therapeutic target for neurodegenerative diseases.
  • Sig-1R-mediated regulation of p35 degradation provides a mechanistic link between ER chaperones, protein turnover, and neuroprotection.
Keywords:
axon growthcdk5myristic acidp35sigma-1 receptor

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