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

First Author  Behesti H Year  2018
Journal  Proc Natl Acad Sci U S A Volume  115
Issue  41 Pages  E9717-E9726
PubMed ID  30242134 Mgi Jnum  J:266179
Mgi Id  MGI:6202779 Doi  10.1073/pnas.1809382115
Citation  Behesti H, et al. (2018) ASTN2 modulates synaptic strength by trafficking and degradation of surface proteins. Proc Natl Acad Sci U S A 115(41):E9717-E9726
abstractText  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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