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Schizophrenia is a polygenic disorder with common, rare, and structural variants. These variants each contribute only a small fraction of overall risk for developing the disease. To improve understanding of synaptic and functional deterioration shared by large proportions of individuals with schizophrenia, scientists including Melanie Grubisha, MD, PhD; Matthew MacDonald, PhD; David Lewis, MD; and Robert Sweet, MD, from Pitt Psychiatry investigated microtubule-associated protein 2 (MAP2) in cortical regions in schizophrenia. 

“MAP2 is a critical regulator of neuron structure and function, so much so that it in many studies MAP2 immunoreactivity is used as the defining indication of the presence of healthy neurons. Profound reductions of MAP2 immunoreactivity have been consistently identified in the cerebral cortex of individuals with schizophrenia, despite no change in MAP2 protein levels, but until now the meaning of these earlier findings has been unclear. We asked if they might result from phosphorylation of MAP2,which is known to change its immunoreactivity, structure, and function,” said Dr. Grubisha, lead author of the study published in Molecular Psychiatry.
 
The team undertook a phosphoproteomic analysis of MAP2 in primary auditory cortex of postmortem brain tissue from individuals with schizophrenia and unaffected comparison subjects to determine if and where MAP2 structure (through identification of phosphorylated [phospho]peptides) was altered by disease. They quantified 18 MAP2 phosphopeptides, of which nine were significantly altered in subjects with schizophrenia. The MAP2 phosphopeptides were grouped into three modules, each with a distinct relationship to dendritic spine loss, synaptic protein levels, and clinical function in schizophrenia subjects. One of the modules was negatively correlated with these measures and contained the most hyperphosphorylated site in schizophrenia, serine1782. 

The scientists confirmed that phosphorylation of serine 1782 reduces binding of MAP2 to microtubules (a primary function of MAP2), and in a mouse genetically altered to mimic the effect of phosphorylation of serine 1782, they found impairments in neuronal architecture, including reduced spine density. Because only a limited number of MAP2 interacting proteins have been previously identified, the scientists combined co-immunoprecipitation with mass spectrometry to characterize the MAP2 interactome in the mouse brain. The MAP2 interactome was enriched for proteins involved in protein translation. Consistent with this, they found that schizophrenia subjects with low immunoreactivity for MAP2, and in whom phosphorylation at serine 1782 was high, had lower levels of synaptic proteins relative to unaffected comparison subjects and to schizophrenia subjects with normal MAP2 immunoreactivity. This pattern of reduced synaptic protein levels was recapitulated in the genetically altered mice.

“MAP2 phosphorylation is regulated downstream of multiple identified schizophrenia risk genes, suggesting that MAP2 pathology may represent a point of pathologic convergence in schizophrenia. Our findings suggest a new conceptual framework for schizophrenia in which MAP2 function is altered, leading to impairments of neuronal structure and synaptic protein synthesis. This convergent pathology represents an exciting new rational therapeutic target to prevent or reverse impairments seen in schizophrenia,” said Robert Sweet, MD, the study’s senior author.

MAP2 is differentially phosphorylated in schizophrenia, altering its function
Grubisha MJ, Sun X, MacDonald ML, Garver M, Sun Z, Paris KA, Patel DS, DeGiosio RA, Lewis DA, Yates NA, Camacho C, Homanics GE, Ding Y, Sweet RA. Molecular Psychiatry (2021). Published February 1, 2021 https://doi.org/10.1038/s41380-021-01034-z