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Quantitative Proteomic Analysis Reveals apoE4-Dependent Phosphorylation of the Actin-Regulating Protein VASP.
Cakir, Zeynep; Lord, Samuel J; Zhou, Yuan; Jang, Gwendolyn M; Polacco, Benjamin J; Eckhardt, Manon; Jimenez-Morales, David; Newton, Billy W; Orr, Adam L; Johnson, Jeffrey R; da Cruz, Alexandre; Mullins, R Dyche; Krogan, Nevan J; Mahley, Robert W; Swaney, Danielle L.
Afiliação
  • Cakir Z; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, California, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA; Gladstone Institute of Data Science and Biotechnology, Gladston
  • Lord SJ; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA; Howard Hughes Medical Institute, San Francisco, California, USA.
  • Zhou Y; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, California, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA; Gladstone Institute of Data Science and Biotechnology, Gladston
  • Jang GM; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, California, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA; Gladstone Institute of Data Science and Biotechnology, Gladston
  • Polacco BJ; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, California, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA; Gladstone Institute of Data Science and Biotechnology, Gladston
  • Eckhardt M; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, California, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA; Gladstone Institute of Data Science and Biotechnology, Gladston
  • Jimenez-Morales D; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, California, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA; Gladstone Institute of Data Science and Biotechnology, Gladston
  • Newton BW; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, California, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA; Gladstone Institute of Data Science and Biotechnology, Gladston
  • Orr AL; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, California, USA.
  • Johnson JR; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, California, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA; Gladstone Institute of Data Science and Biotechnology, Gladston
  • da Cruz A; GABAeron, Inc, San Francisco, California, USA.
  • Mullins RD; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA; Howard Hughes Medical Institute, San Francisco, California, USA.
  • Krogan NJ; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, California, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA; Gladstone Institute of Data Science and Biotechnology, Gladston
  • Mahley RW; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, California, USA; Departments of Pathology and Medicine, University of California San Francisco, San Francisco, California, USA.
  • Swaney DL; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, California, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA; Gladstone Institute of Data Science and Biotechnology, Gladston
Mol Cell Proteomics ; 22(5): 100541, 2023 05.
Article em En | MEDLINE | ID: mdl-37019383
ABSTRACT
Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease. While neurons generally produce a minority of the apoE in the central nervous system, neuronal expression of apoE increases dramatically in response to stress and is sufficient to drive pathology. Currently, the molecular mechanisms of how apoE4 expression may regulate pathology are not fully understood. Here, we expand upon our previous studies measuring the impact of apoE4 on protein abundance to include the analysis of protein phosphorylation and ubiquitylation signaling in isogenic Neuro-2a cells expressing apoE3 or apoE4. ApoE4 expression resulted in a dramatic increase in vasodilator-stimulated phosphoprotein (VASP) S235 phosphorylation in a protein kinase A (PKA)-dependent manner. This phosphorylation disrupted VASP interactions with numerous actin cytoskeletal and microtubular proteins. Reduction of VASP S235 phosphorylation via PKA inhibition resulted in a significant increase in filopodia formation and neurite outgrowth in apoE4-expressing cells, exceeding levels observed in apoE3-expressing cells. Our results highlight the pronounced and diverse impact of apoE4 on multiple modes of protein regulation and identify protein targets to restore apoE4-related cytoskeletal defects.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Apolipoproteína E4 / Doença de Alzheimer Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Apolipoproteína E4 / Doença de Alzheimer Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article