MAP2 is Hyperphosphorylated in Schizophrenia and Alters its Function

Abstract Schizophrenia (Sz) is highly polygenic disorder, with common, rare, and structural variants each contributing only a small fraction of overall disease risk. Thus, there is a need to identify downstream points of convergence that can be targeted with therapeutics. Profound reduction of Microtubule-associated Protein 2 (MAP2) immunoreactivity (MAP2-IR) is present in ~60% of individuals with Sz, despite no change in MAP2 protein levels. MAP2 is phosphorylated downstream of multiple receptors and kinases identified as Sz risk genes, altering its immunoreactivity and function. Using an unbiased phosphoproteomics approach we quantified 18 MAP2 phosphopeptides, 10 of which were significantly altered in Sz subjects with low MAP2-IR. Network analysis grouped MAP2 phosphorylations into 3 modules, each with a distinct relationship to dendritic spine loss, synaptic protein levels, and clinical function in Sz subjects. We then investigated the most hyperphosphorylated site in Sz, serine1782 (pS1782). Computational modeling predicted phosphorylation of S1782 reduces binding of MAP2 to microtubules, which was confirmed experimentally. Because only a limited number of MAP2 interacting proteins have been previously identified, we combined co-immunoprecipitation with mass spectrometry to characterize the MAP2 interactome in mouse brain. The MAP2 interactome was enriched for proteins comprising the ribosomal complex, including FMRP. This association was shown to be functional as overexpression of wildtype and phosphomimetic MAP2 reduced protein synthesis in vitro. These findings provide a new conceptual framework for Sz in which a large proportion of affected individuals may have a “MAP2opathy” – in which, hyperphosphorylation of MAP2 may mediate impairments of neuronal structure and function.