Regulation of microtubule dynamics and functions

Team Publications

Year of publication 2018

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 (2018 Nov 12)

Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport.

The EMBO journal. : DOI : e100440 Learn more

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.

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Vandana Shashi, Maria M Magiera, Dennis Klein, Maha Zaki, Kelly Schoch, Sabine Rudnik-Schöneborn, Andrew Norman, Osorio Lopes Abath Neto, Marina Dusl, Xidi Yuan, Luca Bartesaghi, Patrizia De Marco, Ahmed A Alfares, Ronit Marom, Stefan T Arold, Francisco J Guzmán-Vega, Loren Dm Pena, Edward C Smith, Maja Steinlin, Mohamed Oe Babiker, Payam Mohassel, A Reghan Foley, Sandra Donkervoort, Rupleen Kaur, Partha S Ghosh, Valentina Stanley, Damir Musaev, Caroline Nava, Cyril Mignot, Boris Keren, Marcello Scala, Elisa Tassano, Paolo Picco, Paola Doneda, Chiara Fiorillo, Mahmoud Y Issa, Ali Alassiri, Ahmed Alahmad, Amanda Gerard, Pengfei Liu, Yaping Yang, Birgit Ertl-Wagner, Peter G Kranz, Ingrid M Wentzensen, Rolf Stucka, Nicholas Stong, Andrew S Allen, David B Goldstein, , Benedikt Schoser, Kai M Rösler, Majid Alfadhel, Valeria Capra, Roman Chrast, Tim M Strom, Erik-Jan Kamsteeg, Carsten G Bönnemann, Joseph G Gleeson, Rudolf Martini, Carsten Janke, Jan Senderek (2018 Nov 12)

Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.

The EMBO journal. : DOI : e100540 Learn more

A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the () mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation. The human disease mainly affected the cerebellum, spinal motor neurons, and peripheral nerves. We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in mice, which thus recapitulated key features of the human disease. Our findings link human neurodegeneration to tubulin polyglutamylation, entailing this post-translational modification as a potential target for drug development for neurodegenerative disorders.

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Nirakar Basnet, Hana Nedozralova, Alvaro H Crevenna, Satish Bodakuntla, Thomas Schlichthaerle, Michael Taschner, Giovanni Cardone, Carsten Janke, Ralf Jungmann, Maria M Magiera, Christian Biertümpfel, Naoko Mizuno (2018 Oct 20)

Direct induction of microtubule branching by microtubule nucleation factor SSNA1.

Nature cell biology : 1172-1180 : DOI : 10.1038/s41556-018-0199-8 Learn more

Microtubules are central elements of the eukaryotic cytoskeleton that often function as part of branched networks. Current models for branching include nucleation of new microtubules from severed microtubule seeds or from γ-tubulin recruited to the side of a pre-existing microtubule. Here, we found that microtubules can be directly remodelled into branched structures by the microtubule-remodelling factor SSNA1 (also known as NA14 or DIP13). The branching activity of SSNA1 relies on its ability to self-assemble into fibrils in a head-to-tail fashion. SSNA1 fibrils guide protofilaments of a microtubule to split apart to form daughter microtubules. We further found that SSNA1 localizes at axon branching sites and has a key role in neuronal development. SSNA1 mutants that abolish microtubule branching in vitro also fail to promote axon development and branching when overexpressed in neurons. We have, therefore, discovered a mechanism for microtubule branching and implicated its role in neuronal development.

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Maria M Magiera, Puja Singh, Carsten Janke (2018 May 31)

SnapShot: Functions of Tubulin Posttranslational Modifications.

Cell : 1552-1552.e1 : DOI : 10.1016/j.cell.2018.05.032 Learn more

Post-translational modification of tubulin offers a mechanism for functional diversification of microtubules and regulation in a variety of physiological contexts. This SnapShot recaps the current state of understanding of tubulin posttranslational modifications and their functions in the regulation of biological processes. To view this SnapShot, open or download the PDF.

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