ASTN2 modulates synaptic strength by trafficking and degradation of surface proteins.
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.
['Behesti|Hourinaz|H|', 'Fore|Taylor R|TR|', 'Wu|Peter|P|', 'Horn|Zachi|Z|', 'Leppert|Mary|M|', 'Hull|Court|C|', 'Hatten|Mary E|ME|0000-0001-9059-660X']
D000818:Animals D002465:Cell Movement D002478:Cells, Cultured D056915:DNA Copy Number Variations D004705:Endocytosis D006023:Glycoproteins D006801:Humans D051379:Mice D008810:Mice, Inbred C57BL D009419:Nerve Tissue Proteins D065886:Neurodevelopmental Disorders D021381:Protein Transport D059748:Proteolysis D011689:Purkinje Cells D013569:Synapses
protein degradation autism spectrum disorder cerebellum protein trafficking synapse