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BDNF Induces Striatal-Enriched Protein Tyrosine Phosphatase 61 Degradation Through the Proteasome

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Abstract

Brain-derived neurotrophic factor (BDNF) promotes synaptic strengthening through the regulation of kinase and phosphatase activity. Conversely, striatal-enriched protein tyrosine phosphatase (STEP) opposes synaptic strengthening through inactivation or internalization of signaling molecules. Here, we investigated whether BDNF regulates STEP levels/activity. BDNF induced a reduction of STEP61 levels in primary cortical neurons, an effect that was prevented by inhibition of tyrosine kinases, phospholipase C gamma, or the ubiquitin-proteasome system (UPS). The levels of pGluN2BTyr1472 and pERK1/2Thr202/Tyr204, two STEP substrates, increased in BDNF-treated cultures, and blockade of the UPS prevented STEP61 degradation and reduced BDNF-induced GluN2B and ERK1/2 phosphorylation. Moreover, brief or sustained cell depolarization reduced STEP61 levels in cortical neurons by different mechanisms. BDNF also promoted UPS-mediated STEP61 degradation in cultured striatal and hippocampal neurons. In contrast, nerve growth factor and neurotrophin-3 had no effect on STEP61 levels. Our results thus indicate that STEP61 degradation is an important event in BDNF-mediated effects.

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Acknowledgments

We are very grateful to Ana López and Maria Teresa Muñoz for their technical support and Dr. Cristina Malagelada and to laboratory members for helpful discussions and critical reading of the manuscript. This work was supported by projects PI10/01072, PI13/01250, and RD12/0019/0002, integrated in the “Plan Nacional de I + D + I y cofinanciado por el ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER),” Ministerio de Ciencia e Innovación, Spain (grants SAF2012-39142 to S.G. and SAF2011-29507 to J.A.), Generalitat de Catalunya, Spain (grant 2009SGR-00326 to J.A.), and the National Institutes of Health (grants MH091037 and MH52711 to P.J.L.). A.S. was supported by Ministerio de Economia y Competitividad, Spain (Juan de la Cierva subprogram, grant JCI-2010-08207) and S.T. by Generalitat de Catalunya, Spain (grant AGAUR ST067914).

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    1. Departament de Biologia Cel · lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain

      Ana Saavedra, Mar Puigdellívol, Shiraz Tyebji, Silvia Ginés, Jordi Alberch & Esther Pérez-Navarro

    2. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain

      Ana Saavedra, Mar Puigdellívol, Shiraz Tyebji, Silvia Ginés, Jordi Alberch & Esther Pérez-Navarro

    3. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

      Ana Saavedra, Mar Puigdellívol, Shiraz Tyebji, Silvia Ginés, Jordi Alberch & Esther Pérez-Navarro

    4. Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT, 06520, USA

      Pradeep Kurup, Jian Xu & Paul J. Lombroso

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    Mar Puigdellívol and Shiraz Tyebji contributed equally to this work.

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    Saavedra, A., Puigdellívol, M., Tyebji, S. et al. BDNF Induces Striatal-Enriched Protein Tyrosine Phosphatase 61 Degradation Through the Proteasome. Mol Neurobiol 53, 4261–4273 (2016). https://doi.org/10.1007/s12035-015-9335-7

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