VCP and ATL1 regulate endoplasmic reticulum and protein synthesis for dendritic spine formation

Nat Commun. 2016 Mar 17;7:11020. doi: 10.1038/ncomms11020.

Abstract

Imbalanced protein homeostasis, such as excessive protein synthesis and protein aggregation, is a pathogenic hallmark of a range of neurological disorders. Here, using expression of mutant proteins, a knockdown approach and disease mutation knockin mice, we show that VCP (valosin-containing protein), together with its cofactor P47 and the endoplasmic reticulum (ER) morphology regulator ATL1 (Atlastin-1), regulates tubular ER formation and influences the efficiency of protein synthesis to control dendritic spine formation in neurons. Strengthening the significance of protein synthesis in dendritic spinogenesis, the translation blocker cyclohexamide and the mTOR inhibitor rapamycin reduce dendritic spine density, while a leucine supplement that increases protein synthesis ameliorates the dendritic spine defects caused by Vcp and Atl1 deficiencies. Because VCP and ATL1 are the causative genes of several neurodegenerative and neurodevelopmental disorders, we suggest that impaired ER formation and inefficient protein synthesis are significant in the pathogenesis of multiple neurological disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Cell Cycle Proteins / metabolism*
  • Cycloheximide / pharmacology
  • Dendritic Spines / drug effects
  • Dendritic Spines / metabolism*
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Gene Knock-In Techniques
  • Gene Knockdown Techniques
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Ion Channels / metabolism
  • Leucine / pharmacology
  • Membrane Proteins / metabolism*
  • Mice
  • Mutation / genetics
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / ultrastructure
  • Protein Biosynthesis* / drug effects
  • Proteins / metabolism
  • Proteolysis / drug effects
  • Rats
  • Sirolimus / pharmacology
  • Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins / metabolism
  • Synapses / drug effects
  • Synapses / metabolism
  • Valosin Containing Protein
  • rab GTP-Binding Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Ion Channels
  • Membrane Proteins
  • Nsfl1c protein, rat
  • Proteins
  • Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins
  • Ufd1 protein, mouse
  • atlastin-1 protein, mouse
  • Cycloheximide
  • Adenosine Triphosphatases
  • Rab10 protein, mouse
  • Valosin Containing Protein
  • Vcp protein, mouse
  • Vcp protein, rat
  • rab GTP-Binding Proteins
  • Leucine
  • Sirolimus