MAP2 is differentially phosphorylated in schizophrenia, altering its function

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Schizophrenia (Sz) is a complex polygenic disorder with unclear underlying mechanisms.
• Reduced microtubule-associated protein 2 (MAP2) immunoreactivity (MAP2-IR) is observed in Sz patients, independent of total MAP2 protein levels.

Purpose of the Study:

• To investigate the role of MAP2 phosphorylation in schizophrenia pathogenesis.
• To identify downstream molecular and cellular consequences of altered MAP2 function in Sz.

Main Methods:

• Unbiased phosphoproteomics to quantify MAP2 phosphopeptides in Sz subjects.
• Network analysis to link phosphopeptides to clinical and cellular phenotypes.
• Computational modeling and experimental validation of MAP2 phosphorylation effects on microtubule binding.
• Co-immunoprecipitation and mass spectrometry to identify the MAP2 interactome.
• Generation and analysis of a phosphomimetic MAP2 transgenic mouse model (S1782E).

Main Results:

• Nine out of 18 quantified MAP2 phosphopeptides were significantly altered in Sz subjects.
• MAP2 phosphopeptides correlated with dendritic spine loss, synaptic protein levels, and clinical function.
• Phosphorylation at serine 1782 (pS1782) was increased in Sz, impairing MAP2 binding to microtubules.
• S1782E mice exhibited reduced dendritic complexity and spine density.
• The MAP2 interactome is enriched for protein translation factors, and altered MAP2 function reduced protein synthesis.
• Low MAP2-IR in Sz subjects correlated with reduced synaptic protein levels, a phenotype mirrored in S1782E mice.

Conclusions:

• Altered MAP2 phosphorylation, termed "MAP2opathy," is a significant factor in schizophrenia.
• This pathway impacts neuronal structure, synaptic protein synthesis, and overall brain function.
• Targeting MAP2 phosphorylation presents a potential therapeutic strategy for schizophrenia.