Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport

Maria M Magiera, Satish Bodakuntla, Jakub Žiak, Sabrina Lacomme, Patricia Marques Sousa, Sophie Leboucher, Torben J Hausrat, Christophe Bosc, Annie Andrieux, Matthias Kneussel, Marc Landry, André Calas, Martin Balastik, Carsten Janke
EMBO J. 2018-11-12; 37(23):
DOI: 10.15252/embj.2018100440

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1. EMBO J. 2018 Dec 3;37(23). pii: e100440. doi: 10.15252/embj.2018100440. Epub 2018
Nov 12.

Excessive tubulin polyglutamylation causes neurodegeneration and perturbs
neuronal transport.

Magiera MM(1)(2), Bodakuntla S(3)(2), Žiak J(4)(5), Lacomme S(6), Marques Sousa
P(3)(2), Leboucher S(3)(2), Hausrat TJ(7), Bosc C(8)(9), Andrieux A(8)(9),
Kneussel M(7), Landry M(10), Calas A(10), Balastik M(4), Janke C(1)(2).

Author information:
(1)Institut Curie, CNRS UMR3348, PSL Research University, Orsay, France
(2)Université Paris-Saclay, CNRS UMR3348, Université Paris Sud, Orsay, France.
(3)Institut Curie, CNRS UMR3348, PSL Research University, Orsay, France.
(4)Department of Molecular Neurobiology, Institute of Physiology, Czech Academy
of Sciences, Prague 4, Czech Republic.
(5)Faculty of Science, Charles University, Prague 2, Czech Republic.
(6)Bordeaux Imaging Center, BIC, UMS 3420, Université Bordeaux, Bordeaux, France.
(7)Center for Molecular Neurobiology (ZMNH), University Medical Center
Hamburg-Eppendorf, Hamburg, Germany.
(8)Grenoble Institut des Neurosciences, GIN, Université Grenoble Alpes, Grenoble,
(9)Inserm U1216, Grenoble, France.
(10)Interdisciplinary Institute for Neuroscience, CNRS UMR5297, Université
Bordeaux, Bordeaux, France.

Comment in
Nat Rev Mol Cell Biol. 2019 Jan;20(1):1.
Curr Biol. 2019 Jan 7;29(1):R28-R30.

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.

© 2018 The Authors.

DOI: 10.15252/embj.2018100440
PMCID: PMC6276888
PMID: 30420556 [Indexed for MEDLINE]

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