-
Something wrong with this record ?
Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport
MM. Magiera, S. Bodakuntla, J. Žiak, S. Lacomme, P. Marques Sousa, S. Leboucher, TJ. Hausrat, C. Bosc, A. Andrieux, M. Kneussel, M. Landry, A. Calas, M. Balastik, C. Janke,
Language English Country Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
NLK
Free Medical Journals
from 1982 to 1 year ago
Nature Open Access
from 2003-10-01
PubMed Central
from 1982
Europe PubMed Central
from 1982 to 1 year ago
Open Access Digital Library
from 1997-01-01
Open Access Digital Library
from 1997-01-01
Medline Complete (EBSCOhost)
from 1997-01-02 to 1 year ago
Wiley Free Content
from 1997 to 1 year ago
Springer Nature OA/Free Journals
from 2003-10-01
- MeSH
- Biological Transport, Active genetics MeSH
- Mice, Knockout MeSH
- Mice MeSH
- Neurodegenerative Diseases genetics metabolism pathology MeSH
- Peptide Synthases genetics metabolism MeSH
- Peptides genetics metabolism MeSH
- Protein Processing, Post-Translational * MeSH
- Nerve Tissue Proteins genetics metabolism MeSH
- Purkinje Cells metabolism pathology MeSH
- Tubulin genetics metabolism MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
Bordeaux Imaging Center BIC UMS 3420 Université Bordeaux Bordeaux France
Center for Molecular Neurobiology University Medical Center Hamburg Eppendorf Hamburg Germany
Interdisciplinary Institute for Neuroscience CNRS UMR5297 Université Bordeaux Bordeaux France
References provided by Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc19045142
- 003
- CZ-PrNML
- 005
- 20200120084946.0
- 007
- ta
- 008
- 200109s2018 xxk f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.15252/embj.2018100440 $2 doi
- 035 __
- $a (PubMed)30420556
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a xxk
- 100 1_
- $a Magiera, Maria M $u Institut Curie, CNRS UMR3348, PSL Research University, Orsay, France maria.magiera@curie.fr carsten.janke@curie.fr. Université Paris-Saclay, CNRS UMR3348, Université Paris Sud, Orsay, France.
- 245 10
- $a Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport / $c MM. Magiera, S. Bodakuntla, J. Žiak, S. Lacomme, P. Marques Sousa, S. Leboucher, TJ. Hausrat, C. Bosc, A. Andrieux, M. Kneussel, M. Landry, A. Calas, M. Balastik, C. Janke,
- 520 9_
- $a 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.
- 650 _2
- $a zvířata $7 D000818
- 650 _2
- $a aktivní transport $x genetika $7 D001693
- 650 _2
- $a myši $7 D051379
- 650 _2
- $a myši knockoutované $7 D018345
- 650 _2
- $a proteiny nervové tkáně $x genetika $x metabolismus $7 D009419
- 650 _2
- $a neurodegenerativní nemoci $x genetika $x metabolismus $x patologie $7 D019636
- 650 _2
- $a peptidsynthasy $x genetika $x metabolismus $7 D010453
- 650 _2
- $a peptidy $x genetika $x metabolismus $7 D010455
- 650 12
- $a posttranslační úpravy proteinů $7 D011499
- 650 _2
- $a Purkyňovy buňky $x metabolismus $x patologie $7 D011689
- 650 _2
- $a tubulin $x genetika $x metabolismus $7 D014404
- 655 _2
- $a časopisecké články $7 D016428
- 655 _2
- $a práce podpořená grantem $7 D013485
- 700 1_
- $a Bodakuntla, Satish $u Institut Curie, CNRS UMR3348, PSL Research University, Orsay, France. Université Paris-Saclay, CNRS UMR3348, Université Paris Sud, Orsay, France.
- 700 1_
- $a Žiak, Jakub $u Department of Molecular Neurobiology, Institute of Physiology, Czech Academy of Sciences, Prague 4, Czech Republic. Faculty of Science, Charles University, Prague 2, Czech Republic.
- 700 1_
- $a Lacomme, Sabrina $u Bordeaux Imaging Center, BIC, UMS 3420, Université Bordeaux, Bordeaux, France.
- 700 1_
- $a Marques Sousa, Patricia $u Institut Curie, CNRS UMR3348, PSL Research University, Orsay, France. Université Paris-Saclay, CNRS UMR3348, Université Paris Sud, Orsay, France.
- 700 1_
- $a Leboucher, Sophie $u Institut Curie, CNRS UMR3348, PSL Research University, Orsay, France. Université Paris-Saclay, CNRS UMR3348, Université Paris Sud, Orsay, France.
- 700 1_
- $a Hausrat, Torben J $u Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- 700 1_
- $a Bosc, Christophe $u Grenoble Institut des Neurosciences, GIN, Université Grenoble Alpes, Grenoble, France. Inserm U1216, Grenoble, France.
- 700 1_
- $a Andrieux, Annie $u Grenoble Institut des Neurosciences, GIN, Université Grenoble Alpes, Grenoble, France. Inserm U1216, Grenoble, France.
- 700 1_
- $a Kneussel, Matthias $u Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- 700 1_
- $a Landry, Marc $u Interdisciplinary Institute for Neuroscience, CNRS UMR5297, Université Bordeaux, Bordeaux, France.
- 700 1_
- $a Calas, André $u Interdisciplinary Institute for Neuroscience, CNRS UMR5297, Université Bordeaux, Bordeaux, France.
- 700 1_
- $a Balastik, Martin $u Department of Molecular Neurobiology, Institute of Physiology, Czech Academy of Sciences, Prague 4, Czech Republic.
- 700 1_
- $a Janke, Carsten $u Institut Curie, CNRS UMR3348, PSL Research University, Orsay, France maria.magiera@curie.fr carsten.janke@curie.fr. Université Paris-Saclay, CNRS UMR3348, Université Paris Sud, Orsay, France.
- 773 0_
- $w MED00001509 $t The EMBO journal $x 1460-2075 $g Roč. 37, č. 23 (2018)
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/30420556 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y a $z 0
- 990 __
- $a 20200109 $b ABA008
- 991 __
- $a 20200120085322 $b ABA008
- 999 __
- $a ok $b bmc $g 1483411 $s 1083815
- BAS __
- $a 3
- BAS __
- $a PreBMC
- BMC __
- $a 2018 $b 37 $c 23 $e 20181112 $i 1460-2075 $m EMBO journal $n EMBO J $x MED00001509
- LZP __
- $a Pubmed-20200109