Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport
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Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport. / Magiera, Maria M; Bodakuntla, Satish; Žiak, Jakub; Lacomme, Sabrina; Marques Sousa, Patricia; Leboucher, Sophie; Hausrat, Torben J; Bosc, Christophe; Andrieux, Annie; Kneussel, Matthias; Landry, Marc; Calas, André; Balastik, Martin; Janke, Carsten.
in: EMBO J, Jahrgang 37, Nr. 23, 03.12.2018, S. e100440.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport
AU - Magiera, Maria M
AU - Bodakuntla, Satish
AU - Žiak, Jakub
AU - Lacomme, Sabrina
AU - Marques Sousa, Patricia
AU - Leboucher, Sophie
AU - Hausrat, Torben J
AU - Bosc, Christophe
AU - Andrieux, Annie
AU - Kneussel, Matthias
AU - Landry, Marc
AU - Calas, André
AU - Balastik, Martin
AU - Janke, Carsten
N1 - © 2018 The Authors.
PY - 2018/12/3
Y1 - 2018/12/3
N2 - Posttranslational modifications of tubulin are emerging regulators of microtubule functions. We have shown earlier that upregulated polyglutamylation is linked to rapid degeneration of Purkinje cells in mice with a mutation in the deglutamylating enzyme CCP1. How polyglutamylation leads to degeneration, whether it affects multiple neuron types, or which physiological processes it regulates in healthy neurons has remained unknown. Here, we demonstrate that excessive polyglutamylation induces neurodegeneration in a cell-autonomous manner and can occur in many parts of the central nervous system. Degeneration of selected neurons in CCP1-deficient mice can be fully rescued by simultaneous knockout of the counteracting polyglutamylase TTLL1. Excessive polyglutamylation reduces the efficiency of neuronal transport in cultured hippocampal neurons, suggesting that impaired cargo transport plays an important role in the observed degenerative phenotypes. We thus establish polyglutamylation as a cell-autonomous mechanism for neurodegeneration that might be therapeutically accessible through manipulation of the enzymes that control this posttranslational modification.
AB - Posttranslational modifications of tubulin are emerging regulators of microtubule functions. We have shown earlier that upregulated polyglutamylation is linked to rapid degeneration of Purkinje cells in mice with a mutation in the deglutamylating enzyme CCP1. How polyglutamylation leads to degeneration, whether it affects multiple neuron types, or which physiological processes it regulates in healthy neurons has remained unknown. Here, we demonstrate that excessive polyglutamylation induces neurodegeneration in a cell-autonomous manner and can occur in many parts of the central nervous system. Degeneration of selected neurons in CCP1-deficient mice can be fully rescued by simultaneous knockout of the counteracting polyglutamylase TTLL1. Excessive polyglutamylation reduces the efficiency of neuronal transport in cultured hippocampal neurons, suggesting that impaired cargo transport plays an important role in the observed degenerative phenotypes. We thus establish polyglutamylation as a cell-autonomous mechanism for neurodegeneration that might be therapeutically accessible through manipulation of the enzymes that control this posttranslational modification.
KW - Journal Article
U2 - 10.15252/embj.2018100440
DO - 10.15252/embj.2018100440
M3 - SCORING: Journal article
C2 - 30420556
VL - 37
SP - e100440
JO - EMBO J
JF - EMBO J
SN - 0261-4189
IS - 23
ER -