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
  • 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.