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MAP2 is Differentially Phosphorylated in Schizophrenia, Altering its Function

View ORCID ProfileMJ Grubisha, X Sun, ML MacDonald, M Garver, Z Sun, KA Paris, DS Patel, RA DeGiosio, DA Lewis, NA Yates, View ORCID ProfileC Camacho, GE Homanics, Y Ding, RA Sweet
doi: https://doi.org/10.1101/683912
MJ Grubisha
1Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA
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  • ORCID record for MJ Grubisha
X Sun
1Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA
2Tsinghua MD Program, Tsinghua Unviersity School of Medicine, Beijing, China
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ML MacDonald
1Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA
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M Garver
1Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA
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Z Sun
3Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA 15260, USA
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KA Paris
5Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA
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DS Patel
5Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA
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RA DeGiosio
1Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA
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DA Lewis
1Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA
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NA Yates
4Department of Cell Biology, University of Pittsburgh, 3500 Terrace Street, S362 Biomedical Science Tower (South) Pittsburgh, PA, 15261, United States; Biomedical Mass Spectrometry Center, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, PA, 15213-1863, United States
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C Camacho
5Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA
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GE Homanics
6Departments of Anesthesiology and Perioperative Medicine, Pharmacology & Chemical Biology, & Neurobiology, University of Pittsburgh School of Medicine, 3601 Fifth Ave, Pittsburgh, PA 15261, USA
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Y Ding
3Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA 15260, USA
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RA Sweet
1Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA
7Department of Neurology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA
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  • For correspondence: sweetra@upmc.edu
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Abstract

Schizophrenia (Sz) is a 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. Reduction of Microtubule-associated Protein 2 (MAP2) immunoreactivity (MAP2-IR) is present in 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, 9 of which were significantly altered in Sz subjects. Network analysis grouped MAP2 phosphopeptides 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, phosphoserine1782 (pS1782). Computational modeling predicted phosphorylation of S1782 reduces binding of MAP2 to microtubules, which was confirmed experimentally. We generated a transgenic mouse containing a phosphomimetic mutation at S1782 (S1782E) and found reductions in basilar dendritic length and complexity along with reduced spine density. 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 involved in protein translation. These associations were shown to be functional as overexpression of wildtype and phosphomimetic MAP2 reduced protein synthesis in vitro. Finally, we found that Sz subjects with low MAP2-IR had reductions in the levels of synaptic proteins relative to nonpsychiatric control (NPC) subjects and to Sz subjects with normal and MAP2-IR, and this same pattern was recapitulated in S1782E mice. These findings suggest a new conceptual framework for Sz - that a large proportion of individuals have a “MAP2opathy” - in which MAP function is altered by phosphorylation, leading to impairments of neuronal structure, synaptic protein synthesis, and function.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Updated supplementary material, revised discussion

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted December 30, 2020.
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MAP2 is Differentially Phosphorylated in Schizophrenia, Altering its Function
MJ Grubisha, X Sun, ML MacDonald, M Garver, Z Sun, KA Paris, DS Patel, RA DeGiosio, DA Lewis, NA Yates, C Camacho, GE Homanics, Y Ding, RA Sweet
bioRxiv 683912; doi: https://doi.org/10.1101/683912
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MAP2 is Differentially Phosphorylated in Schizophrenia, Altering its Function
MJ Grubisha, X Sun, ML MacDonald, M Garver, Z Sun, KA Paris, DS Patel, RA DeGiosio, DA Lewis, NA Yates, C Camacho, GE Homanics, Y Ding, RA Sweet
bioRxiv 683912; doi: https://doi.org/10.1101/683912

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