2. Academic Validation
  3. Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration

Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration

  • EMBO J. 2018 Dec 3;37(23):e100540. doi: 10.15252/embj.2018100540.
Vandana Shashi 1,  Maria M Magiera 2 3,  Dennis Klein 4,  Maha Zaki 5,  Kelly Schoch 6,  Sabine Rudnik-Schöneborn 7,  Andrew Norman 8,  Osorio Lopes Abath Neto 9,  Marina Dusl 10,  Xidi Yuan 4,  Luca Bartesaghi 11,  Patrizia De Marco 12,  Ahmed A Alfares 13,  Ronit Marom 14 15,  Stefan T Arold 16,  Francisco J Guzmán-Vega 16,  Loren Dm Pena 17 18,  Edward C Smith 19,  Maja Steinlin 20,  Mohamed Oe Babiker 21,  Payam Mohassel 9,  A Reghan Foley 9,  Sandra Donkervoort 9,  Rupleen Kaur 9,  Partha S Ghosh 22,  Valentina Stanley 23,  Damir Musaev 23,  Caroline Nava 24 25,  Cyril Mignot 24 25,  Boris Keren 24 25,  Marcello Scala 12,  Elisa Tassano 12,  Paolo Picco 12,  Paola Doneda 26,  Chiara Fiorillo 12 27,  Mahmoud Y Issa 5,  Ali Alassiri 28,  Ahmed Alahmad 28,  Amanda Gerard 14 15,  Pengfei Liu 14 29,  Yaping Yang 14 29,  Birgit Ertl-Wagner 30,  Peter G Kranz 31,  Ingrid M Wentzensen 32,  Rolf Stucka 10,  Nicholas Stong 33,  Andrew S Allen 34 35,  David B Goldstein 33,  Undiagnosed Diseases Network,  Benedikt Schoser 10,  Kai M Rösler 36,  Majid Alfadhel 37,  Valeria Capra 12,  Roman Chrast 11,  Tim M Strom 38 39,  Erik-Jan Kamsteeg 40,  Carsten G Bönnemann 9,  Joseph G Gleeson 23,  Rudolf Martini 4,  Carsten Janke 41 3,  Jan Senderek 42
Affiliations

Affiliations

  • 1 Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA [email protected] [email protected] [email protected].
  • 2 Institut Curie, CNRS UMR3348, PSL Research University, Orsay, France.
  • 3 CNRS UMR3348, Université Paris Sud, Université Paris-Saclay, Orsay, France.
  • 4 Department of Neurology, Developmental Neurobiology, University Hospital Würzburg, Würzburg, Germany.
  • 5 Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
  • 6 Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
  • 7 Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
  • 8 Department of Clinical Genetics, St. Michael's Hospital, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
  • 9 Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
  • 10 Friedrich Baur Institute at the Department of Neurology, Friedrich Baur Institute, University Hospital, LMU Munich, Munich, Germany.
  • 11 Department of Neuroscience and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
  • 12 IRCCS Istituto Giannina Gaslini, Genova, Italy.
  • 13 Department of Pediatrics, College of Medicine, Qassim University, Qassim, Saudi Arabia.
  • 14 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • 15 Texas Children's Hospital, Houston, TX, USA.
  • 16 Division of Biological and Environmental Sciences and Engineering (BESE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
  • 17 Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 18 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
  • 19 Division of Neurology, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
  • 20 Division of Neuropaediatrics, Development and Rehabilitation, University Children's Hospital, Inselspital, University of Bern, Bern, Switzerland.
  • 21 Neurosciences Centre, Al Jalila Children's Hospital, Dubai, UAE.
  • 22 Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • 23 Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, University of California, San Diego, CA, USA.
  • 24 Department of Genetics, Assistance Publique des Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France.
  • 25 Institut du Cerveau et de la Moelle épinière, Sorbonne Universités, Inserm U1127, CNRS, UMR 7225, UPMC Univ Paris 06, Paris, France.
  • 26 Grande Ospedale Metropolitano Niguarda, Milano, Italy.
  • 27 Università degli Studi di Genova, Genova, Italy.
  • 28 Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
  • 29 Baylor Genetics, Houston, TX, USA.
  • 30 Department of Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
  • 31 Division of Neuroradiology, Department of Radiology, Duke University Medical Center, Durham, NC, USA.
  • 32 GeneDx, Gaithersburg, MD, USA.
  • 33 Institute of Genomic Medicine, Columbia University, New York, NY, USA.
  • 34 Center for Statistical Genetics and Genomics, Duke University Medical Center, Durham, NC, USA.
  • 35 Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.
  • 36 Neuromuscular Centre, University Department of Neurology, Inselspital, Bern, Switzerland.
  • 37 Genetics Division, Department of Pediatrics, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
  • 38 Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
  • 39 Institute of Human Genetics, Technische Universität München, Munich, Germany.
  • 40 Department of Human Genetics, Donders Centre for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 41 Institut Curie, CNRS UMR3348, PSL Research University, Orsay, France [email protected] [email protected] [email protected].
  • 42 Friedrich Baur Institute at the Department of Neurology, Friedrich Baur Institute, University Hospital, LMU Munich, Munich, Germany [email protected] [email protected] [email protected].
PMID: 30420557 DOI: 10.15252/embj.2018100540
Abstract

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 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 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.

Keywords

cerebellum; cytosolic carboxypeptidase 1 (CCP1/AGTPBP1/NNA1); motor neuron; neurodegeneration; tubulin polyglutamylation.

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