Autophagy lipidation machinery regulates axonal microtubule dynamics but is dispensable for survival of mammalian neurons

Nat Commun. 2020 Mar 24;11(1):1535. doi: 10.1038/s41467-020-15287-9.

Abstract

Neurons maintain axonal homeostasis via employing a unique organization of the microtubule (MT) cytoskeleton, which supports axonal morphology and provides tracks for intracellular transport. Abnormal MT-based trafficking hallmarks the pathology of neurodegenerative diseases, but the exact mechanism regulating MT dynamics in axons remains enigmatic. Here we report on a regulation of MT dynamics by AuTophaGy(ATG)-related proteins, which previously have been linked to the autophagy pathway. We find that ATG proteins required for LC3 lipid conjugation are dispensable for survival of excitatory neurons and instead regulate MT stability via controlling the abundance of the MT-binding protein CLASP2. This function of ATGs is independent of their role in autophagy and requires the active zone protein ELKS1. Our results highlight a non-canonical role of ATG proteins in neurons and suggest that pharmacological activation of autophagy may not only promote the degradation of cytoplasmic material, but also impair axonal integrity via altering MT stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Autophagy / physiology*
  • Autophagy-Related Protein 5 / genetics
  • Autophagy-Related Protein 5 / metabolism
  • Axons / physiology*
  • Cell Survival
  • Cells, Cultured
  • Gene Knockout Techniques
  • Lipid Metabolism / physiology*
  • Mice
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Microtubules / metabolism*
  • Nerve Tissue Proteins / metabolism
  • Primary Cell Culture
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • rab GTP-Binding Proteins / metabolism

Substances

  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • CLASP2 protein, mouse
  • Erc1 protein, mouse
  • LC3 protein, rat
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Recombinant Proteins
  • rab GTP-Binding Proteins