Deciphering the alteration of MAP2 interactome caused by a schizophrenia-associated phosphorylation
Microtubule-associated protein 2 (MAP2) is a crucial regulator of dendritic structure and neuronal function, orchestrating diverse protein interactions within the microtubule network. We have shown MAP2 is hyperphosphorylated at serine 1782 (S1782) in schizophrenia and phosphomimetic mutation of S17...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-12-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996124003334 |
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| author | Jiali Lyu Matthew L MacDonald Shelby Ruiz Shinnyi Chou Jordan Gilardi Serena C Buchwald Melanie J Grubisha Robert A Sweet |
| author_facet | Jiali Lyu Matthew L MacDonald Shelby Ruiz Shinnyi Chou Jordan Gilardi Serena C Buchwald Melanie J Grubisha Robert A Sweet |
| author_sort | Jiali Lyu |
| collection | DOAJ |
| description | Microtubule-associated protein 2 (MAP2) is a crucial regulator of dendritic structure and neuronal function, orchestrating diverse protein interactions within the microtubule network. We have shown MAP2 is hyperphosphorylated at serine 1782 (S1782) in schizophrenia and phosphomimetic mutation of S1782 in mice (MAP2S1782E) is sufficient to impair dendritic architecture. We sought to determine how this hyperphosphorylation affects the MAP2 interactome to provide insights into the disorder's mechanisms. We investigated the MAP2 interactome using co-immunoprecipitation and mass spectrometry in MAP2S1782E and MAP2WT mice. We found that S1782E MAP2 led to a substantial disruption of protein-protein interactions relative to WT MAP2. Reduced interactions with PDZ domain-containing proteins, calmodulin-binding proteins, ribosome proteins, and kinesin proteins may all contribute to dendritic impairments induced by S1782E, and may be linked to schizophrenia pathogenesis. Interestingly, novel gain-of-function interactions with PPM1L and KLHL8 nominated these as regulators of phosphoS1782 MAP2 abundance and potential therapeutic targets in schizophrenia. |
| format | Article |
| id | doaj-art-73ea272b0e6a461d87af77dfd091cca0 |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-73ea272b0e6a461d87af77dfd091cca02024-12-14T06:29:53ZengElsevierNeurobiology of Disease1095-953X2024-12-01203106731Deciphering the alteration of MAP2 interactome caused by a schizophrenia-associated phosphorylationJiali Lyu0Matthew L MacDonald1Shelby Ruiz2Shinnyi Chou3Jordan Gilardi4Serena C Buchwald5Melanie J Grubisha6Robert A Sweet7School of Medicine, Tsinghua University, China; Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, United States of AmericaTranslational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, United States of America; Health Sciences Mass Spectrometry Core, University of Pittsburgh, United States of AmericaDepartment of Neurobiology, University of Pittsburgh, United States of AmericaTranslational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, United States of AmericaTranslational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, United States of AmericaTranslational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, United States of AmericaTranslational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, United States of AmericaTranslational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, United States of America; Department of Neurology, University of Pittsburgh, United States of America; Corresponding author at: Biomedical Science Tower, Rm W-1645, 3811 O'Hara Street, Pittsburgh, PA 15213-2593, United States of America.Microtubule-associated protein 2 (MAP2) is a crucial regulator of dendritic structure and neuronal function, orchestrating diverse protein interactions within the microtubule network. We have shown MAP2 is hyperphosphorylated at serine 1782 (S1782) in schizophrenia and phosphomimetic mutation of S1782 in mice (MAP2S1782E) is sufficient to impair dendritic architecture. We sought to determine how this hyperphosphorylation affects the MAP2 interactome to provide insights into the disorder's mechanisms. We investigated the MAP2 interactome using co-immunoprecipitation and mass spectrometry in MAP2S1782E and MAP2WT mice. We found that S1782E MAP2 led to a substantial disruption of protein-protein interactions relative to WT MAP2. Reduced interactions with PDZ domain-containing proteins, calmodulin-binding proteins, ribosome proteins, and kinesin proteins may all contribute to dendritic impairments induced by S1782E, and may be linked to schizophrenia pathogenesis. Interestingly, novel gain-of-function interactions with PPM1L and KLHL8 nominated these as regulators of phosphoS1782 MAP2 abundance and potential therapeutic targets in schizophrenia.http://www.sciencedirect.com/science/article/pii/S0969996124003334MAP2ProteomicsProtein-protein interactionPhosphorylation |
| spellingShingle | Jiali Lyu Matthew L MacDonald Shelby Ruiz Shinnyi Chou Jordan Gilardi Serena C Buchwald Melanie J Grubisha Robert A Sweet Deciphering the alteration of MAP2 interactome caused by a schizophrenia-associated phosphorylation Neurobiology of Disease MAP2 Proteomics Protein-protein interaction Phosphorylation |
| title | Deciphering the alteration of MAP2 interactome caused by a schizophrenia-associated phosphorylation |
| title_full | Deciphering the alteration of MAP2 interactome caused by a schizophrenia-associated phosphorylation |
| title_fullStr | Deciphering the alteration of MAP2 interactome caused by a schizophrenia-associated phosphorylation |
| title_full_unstemmed | Deciphering the alteration of MAP2 interactome caused by a schizophrenia-associated phosphorylation |
| title_short | Deciphering the alteration of MAP2 interactome caused by a schizophrenia-associated phosphorylation |
| title_sort | deciphering the alteration of map2 interactome caused by a schizophrenia associated phosphorylation |
| topic | MAP2 Proteomics Protein-protein interaction Phosphorylation |
| url | http://www.sciencedirect.com/science/article/pii/S0969996124003334 |
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