ASTN2 modultes synaptic strength by trafficking and degradation of surface proteins

Hourinaz Behesti, Taylor R. Fore, Peter Wu, Zachi Horn, Mary Leppert, Court Hull, Mary E. Hattena

Research output: Contribution to journalArticlepeer-review

Abstract

Surface protein dynamics dictate synaptic connectivity and function in neuronal circuits. ASTN2, a gene disrupted by copy number variations (CNVs) in neurodevelopmental disorders, including autism spectrum, was previously shown to regulate the surface expression of ASTN1 in glial-guided neuronal migration. Here, we demonstrate that ASTN2 binds to and regulates the surface expression of multiple synaptic proteins in postmigratory neurons by endocytosis, resulting in modulation of synaptic activity. In cerebellar Purkinje cells (PCs), by immunogold electron microscopy, ASTN2 localizes primarily to endocytic and autophagocytic vesicles in the cell soma and in subsets of dendritic spines. Overexpression of ASTN2 in PCs, but not of ASTN2 lacking the FNIII domain, recurrently disrupted by CNVs in patients, including in a family presented here, increases inhibitory and excitatory postsynaptic activity and reduces levels of ASTN2 binding partners. Our data suggest a fundamental role for ASTN2 in dynamic regulation of surface proteins by endocytic trafficking and protein degradation.

Original languageEnglish (US)
Pages (from-to)E9717-E9726
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number41
DOIs
StatePublished - Oct 9 2018
Externally publishedYes

Keywords

  • Autism spectrum disorder
  • Cerebellum
  • Protein degradation
  • Protein trafficking
  • Synapse

ASJC Scopus subject areas

  • General

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