Journal article
Loss of tubulin deglutamylase CCP1 causes infantile‐onset neurodegeneration
The EMBO journal, Vol.37(23), e100540
11/12/2018
DOI: 10.15252/embj.2018100540
PMCID: PMC6276871
PMID: 30420557
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
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.
Details
- Title: Subtitle
- Loss of tubulin deglutamylase CCP1 causes infantile‐onset neurodegeneration
- Creators
- Vandana Shashi - Duke UniversityMaria M Magiera - Université Paris-SaclayDennis Klein - Universitätsklinikum WürzburgMaha Zaki - National Research CentreKelly Schoch - Duke UniversitySabine Rudnik‐Schöneborn - Medical University InnsbruckAndrew Norman - University Hospitals Bristol NHS Foundation TrustOsorio Lopes Abath Neto - National Institute of Neurological Disorders and StrokeMarina Dusl - Ludwig-Maximilians-Universität MünchenXidi Yuan - Universitätsklinikum WürzburgLuca Bartesaghi - Karolinska InstitutetPatrizia De Marco - Istituto Giannina GasliniAhmed A Alfares - Qassim UniversityRonit Marom - Baylor College of MedicineStefan T Arold - King Abdullah University of Science and TechnologyFrancisco J Guzmán‐Vega - King Abdullah University of Science and TechnologyLoren DM Pena - University of Cincinnati Medical CenterEdward C Smith - Duke UniversityMaja Steinlin - Boston Children's HospitalMohamed OE Babiker - Boston Children's HospitalPayam Mohassel - National Institute of Neurological Disorders and StrokeA Reghan Foley - National Institute of Neurological Disorders and StrokeSandra Donkervoort - National Institute of Neurological Disorders and StrokeRupleen Kaur - National Institute of Neurological Disorders and StrokePartha S Ghosh - Boston Children's HospitalValentina Stanley - University of California, San DiegoDamir Musaev - University of California, San DiegoCaroline Nava - Université Paris CitéCyril Mignot - Université Paris CitéBoris Keren - Université Paris CitéMarcello Scala - Istituto Giannina GasliniElisa Tassano - Istituto Giannina GasliniPaolo Picco - Istituto Giannina GasliniPaola Doneda - Grande Ospedale Metropolitano NiguardaChiara Fiorillo - University of GenoaMahmoud Y Issa - National Research CentreAli Alassiri - King Abdulaziz Medical CityAhmed Alahmad - King Abdulaziz Medical CityAmanda Gerard - Baylor College of MedicinePengfei Liu - Baylor UniversityYaping Yang - Baylor UniversityBirgit Ertl‐Wagner - University of TorontoPeter G Kranz - Duke UniversityIngrid M Wentzensen - GeneDxRolf Stucka - Ludwig-Maximilians-Universität MünchenNicholas Stong - Columbia UniversityAndrew S Allen - Duke UniversityDavid B Goldstein - Columbia UniversityBenedikt Schoser - Ludwig-Maximilians-Universität MünchenKai M Rösler - Ludwig-Maximilians-Universität MünchenMajid Alfadhel - King Abdulaziz Medical CityValeria Capra - King Saud bin Abdulaziz University for Health SciencesRoman Chrast - Istituto Giannina GasliniTim M Strom - Karolinska InstitutetErik‐Jan Kamsteeg - Radboud University Medical CenterCarsten G Bönnemann - Radboud University NijmegenJoseph G Gleeson - University of CaliforniaRudolf Martini - University of California, San DiegoCarsten Janke - Université Paris Sciences et LettresUndiagnosed Diseases NetworkJan Senderek - Université Paris-Saclay
- Resource Type
- Journal article
- Publication Details
- The EMBO journal, Vol.37(23), e100540
- Publisher
- John Wiley and Sons Inc
- DOI
- 10.15252/embj.2018100540
- PMID
- 30420557
- PMCID
- PMC6276871
- ISSN
- 0261-4189
- eISSN
- 1460-2075
- 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)
- Alternative title
- Vandana Shashi et al
- Language
- English
- Date published
- 11/12/2018
- Academic Unit
- Pathology
- Record Identifier
- 9984276451902771
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