Loss of tubulin deglutamylase CCP1 causes infantile‐onset neurodegeneration

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; Undiagnosed Dis Network; Jan Senderek

doi:10.15252/embj.2018100540

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Loss of tubulin deglutamylase CCP1 causes infantile‐onset neurodegeneration

Journal article

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Peer reviewed

Loss of tubulin deglutamylase CCP1 causes infantile‐onset neurodegeneration

Vandana Shashi, Maria M Magiera, Dennis Klein, Maha Zaki, Kelly Schoch, Sabine Rudnik-Schöneborn, Andrew Norman, Osorio Lopes Abath Neto, Marina Dusl, Xidi Yuan, …

The EMBO journal, Vol.37(23), p.n/a

03/12/2018

DOI: https://doi.org/10.15252/embj.2018100540

PMCID: PMC6276871

PMID: 30420557

Abstract

AGTPBP1

cerebellum

cytosolic carboxypeptidase 1 (CCP1

Molecular Biology of Disease

motor neuron

neurodegeneration

Neuroscience

NNA1

tubulin polyglutamylation

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 Purkinje cell degeneration ( pcd ) mouse, which lacks deglutamylase CCP 1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP 1 in 13 individuals with infantile‐onset neurodegeneration and confirmed the absence of functional CCP 1 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 pcd 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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Title: Loss of tubulin deglutamylase CCP1 causes infantile‐onset neurodegeneration
Creators - without role: Vandana Shashi - Duke Medical Center
Maria M Magiera - Université Paris Sciences et Lettres
Dennis Klein - Universitätsklinikum Würzburg
Maha Zaki - National Research Centre
Kelly Schoch - Duke Medical Center
Sabine Rudnik-Schöneborn - Medical University Innsbruck
Andrew Norman - University Hospitals Bristol NHS Foundation Trust
Osorio Lopes Abath Neto - National Institute of Neurological Disorders and Stroke
Marina Dusl - Friedrich Baur Stiftung
Xidi Yuan - Universitätsklinikum Würzburg
Luca Bartesaghi - Karolinska Institutet
Patrizia De Marco - Istituti di Ricovero e Cura a Carattere Scientifico
Ahmed A Alfares - Qassim University
Ronit Marom - Texas Children's Hospital
Stefan T Arold - King Abdullah University of Science and Technology
Francisco J Guzmán-Vega - King Abdullah University of Science and Technology
Loren DM Pena - Cincinnati Children's Hospital Medical Center
Edward C Smith - Duke Medical Center
Maja Steinlin - University Children’s Hospital Bern
Mohamed OE Babiker - Al Jalila Foundation
Payam Mohassel - National Institute of Neurological Disorders and Stroke
A Reghan Foley - National Institute of Neurological Disorders and Stroke
Sandra Donkervoort - National Institute of Neurological Disorders and Stroke
Rupleen Kaur - National Institute of Neurological Disorders and Stroke
Partha S Ghosh - Boston Children's Hospital
Valentina Stanley - Howard Hughes Medical Institute
Damir Musaev - Howard Hughes Medical Institute
Caroline Nava - Assistance Publique – Hôpitaux de Paris
Cyril Mignot - Assistance Publique – Hôpitaux de Paris
Boris Keren - Assistance Publique – Hôpitaux de Paris
Marcello Scala - Istituto Giannina Gaslini
Elisa Tassano - Istituto Giannina Gaslini
Paolo Picco - Istituto Giannina Gaslini
Paola Doneda - Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda
Chiara Fiorillo - Istituto Giannina Gaslini
Mahmoud Y Issa - National Research Centre
Ali Alassiri - King Abdulaziz Medical City
Ahmed Alahmad - King Abdulaziz Medical City
Amanda Gerard - Baylor College of Medicine
Pengfei Liu - Baylor College of Medicine
Yaping Yang - Baylor College of Medicine
Birgit Ertl-Wagner - University of Toronto
Peter G Kranz - Duke University Hospital
Ingrid M Wentzensen - GeneDx Gaithersburg MD USA
Rolf Stucka - Friedrich Baur Stiftung
Nicholas Stong - Columbia University
Andrew S Allen - Duke University Hospital
David B Goldstein - Columbia University
Benedikt Schoser - Friedrich Baur Stiftung
Kai M Rösler - University Hospital of Bern
Majid Alfadhel - King Saud bin Abdulaziz University for Health Sciences
Valeria Capra - Istituto Giannina Gaslini
Roman Chrast - Karolinska Institutet
Tim M Strom - Helmholtz Zentrum München
Erik‐Jan Kamsteeg - Radboud University Nijmegen
Carsten G Bönnemann - National Institute of Neurological Disorders and Stroke
Joseph G Gleeson - Howard Hughes Medical Institute
Rudolf Martini - Universitätsklinikum Würzburg
Carsten Janke - Université Paris Sciences et Lettres
Undiagnosed Dis Network
Jan Senderek - Friedrich Baur Stiftung
Publication Details: The EMBO journal, Vol.37(23), p.n/a
Publisher: John Wiley and Sons Inc
Grant note: ANR‐12‐BSV2‐0007; ANR‐10‐LBX‐0038; ANR‐10‐IDEX‐0001‐02 PSL / Agence Nationale de la Recherche (ANR) 2013‐1‐PL BIO‐02‐ICR‐1; 2014‐PL BIO‐11‐ICR‐1 / Institut National Du Cancer (INCa) HHS|NIH|National Institute of Neurological Disorders and Stroke (NINDS) U54HG006504 / Yale Center for Mendelian Disorders Bayerische Gleichstellungsförderung 01GM1511B; 01GM1511D; 01GM1511F / Bundesministerium für Bildung und Forschung (BMBF) Az.10.15.1.021MN / Fritz Thyssen Stiftung (Fritz Thyssen Foundation) Friedrich‐Baur‐Stiftung (Friedrich Baur Stiftung) Osteogenesis Imperfecta Foundation (OIF) R01NS098004; R01NS048453 / HHS|National Institutes of Health (NIH) FR‐16055p / Fondation Vaincre Alzheimer UM1 HG008900 / Broad Joint Center for Mendelian Genomics Institut Curie 1U01HG007672‐01 / NIH Common Fund NIH Clinical Center Swedish StratNeuro program FCC/1/1976‐21 / King Abdullah University of Science and Technology (KAUST) NIH Deputy Director for Intramural Research National Human Genome Research Institute ASTF 148‐2015 / European Molecular Biology Organization (EMBO)
Identifiers: 9921334208331
Academic Unit: King Saud Bin Abdulaziz University for Health Sciences; King Abdulaziz University; King Abdullah University of Science & Technology; King Faisal University; Qassim University
Language: English
Resource Type: Journal article