Publishers Version online available 11/2019 Free by publisher as soon as is submitted to ZB.
Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
EMBO J., accepted (2018)
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Cerebellum ; Cytosolic Carboxypeptidase 1 (ccp1/agtpbp1/nna1) ; Motor Neuron ; Neurodegeneration ; Tubulin Polyglutamylation
Institute(s) Institute of Human Genetics (IHG)