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ASTN2 modulates synaptic strength by trafficking and degradation of surface proteins.

Publication ,  Journal Article
Behesti, H; Fore, TR; Wu, P; Horn, Z; Leppert, M; Hull, C; Hatten, ME
Published in: Proc Natl Acad Sci U S A
October 9, 2018

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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

October 9, 2018

Volume

115

Issue

41

Start / End Page

E9717 / E9726

Location

United States

Related Subject Headings

  • Synapses
  • Purkinje Cells
  • Proteolysis
  • Protein Transport
  • Neurodevelopmental Disorders
  • Nerve Tissue Proteins
  • Mice, Inbred C57BL
  • Mice
  • Humans
  • Glycoproteins
 

Citation

APA
Chicago
ICMJE
MLA
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Behesti, H., Fore, T. R., Wu, P., Horn, Z., Leppert, M., Hull, C., & Hatten, M. E. (2018). ASTN2 modulates synaptic strength by trafficking and degradation of surface proteins. Proc Natl Acad Sci U S A, 115(41), E9717–E9726. https://doi.org/10.1073/pnas.1809382115
Behesti, Hourinaz, Taylor R. Fore, Peter Wu, Zachi Horn, Mary Leppert, Court Hull, and Mary E. Hatten. “ASTN2 modulates synaptic strength by trafficking and degradation of surface proteins.Proc Natl Acad Sci U S A 115, no. 41 (October 9, 2018): E9717–26. https://doi.org/10.1073/pnas.1809382115.
Behesti H, Fore TR, Wu P, Horn Z, Leppert M, Hull C, et al. ASTN2 modulates synaptic strength by trafficking and degradation of surface proteins. Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):E9717–26.
Behesti, Hourinaz, et al. “ASTN2 modulates synaptic strength by trafficking and degradation of surface proteins.Proc Natl Acad Sci U S A, vol. 115, no. 41, Oct. 2018, pp. E9717–26. Pubmed, doi:10.1073/pnas.1809382115.
Behesti H, Fore TR, Wu P, Horn Z, Leppert M, Hull C, Hatten ME. ASTN2 modulates synaptic strength by trafficking and degradation of surface proteins. Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):E9717–E9726.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

October 9, 2018

Volume

115

Issue

41

Start / End Page

E9717 / E9726

Location

United States

Related Subject Headings

  • Synapses
  • Purkinje Cells
  • Proteolysis
  • Protein Transport
  • Neurodevelopmental Disorders
  • Nerve Tissue Proteins
  • Mice, Inbred C57BL
  • Mice
  • Humans
  • Glycoproteins