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

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.

SUBMITTER: Behesti H

PROVIDER: S-EPMC6187130 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Behesti Hourinaz H Fore Taylor R TR Wu Peter P Horn Zachi Z Leppert Mary M Hull Court C Hatten Mary E ME

Proceedings of the National Academy of Sciences of the United States of America 20180921 41

Surface protein dynamics dictate synaptic connectivity and function in neuronal circuits. <i>ASTN2</i>, 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 ...[more]

PMID: 30242134

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

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

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