Event:

Microtubules are key components of the neuronal cytoskeleton and play pivotal roles in many aspects of neuronal physiology. How different functions of microtubules could be regulated and coordinated in neurons is one of the key questions in neuronal cell biology. One emerging regulator are tubulin posttranslational modifications (PTMs). We demonstrate that one of these PTMs, polyglutamylation plays a key role in neurons, and deregulation of this PTM induces neurodegeneration.
Polyglutamylation is generated by glutamylases from the TTLL family and removed by
deglutamylases from the CCP family. In mice lacking the deglutamylase CCP1, polyglutamylation is strongly increased in the cerebellum, and cerebellar Purkinje cells die rapidly. When we invalidate one of the key tubulin polyglutamylases in brain, TTLL1, specifically in Purkinje cells of CCP1-KO mice, Purkinje cells survive for the entire life span of the mice. Thus, the degeneration of these neurons in CCP1-KO mice is directly and cellautonomously caused by tubulin hyperglutamylation.
Because only some regions of the central nervous system of CCP1-KO mice are affected by neurodegeneration, we additionally inactivated a second deglutamylase, CCP6. This caused widespread hyperglutamylation, axonal damage and neurodegeneration in many parts of the nervous system, demonstrating that excessive polyglutamylation can cause degeneration of many different types of neurons.
We then measured organelle transport in primary neurons from mice with upregulated
polyglutamylation. We found that transport activity in these neurons was downregulated, but not abolished. The presence of perturbed transport in neurons with perturbed polyglutamylation was further supported by the observation of organelle accumulation in axon tracts of the knockout mice brains. It is therefore likely that perturbed transport is one of the mechanisms that is involved in the degeneration of neurons with upregulated polyglutamylation.
We further discovered biallelic variants of CCP1 in human infantile-onset neurodegeneration, and demonstrate that those variants lead to hyperglutamylation in patients, demonstrating that hyperglutamylation is a valid pathogenic mechanism of human neurodegeneration.
Considering that CCP1-KO mice replicate the symptoms of the human patients, our results obtained from combinatory mouse models suggest that hyperglutamylation could be involved in a rage neurodegenerative disorders, and that manipulation of enzymes controlling this PTM could become a valid therapeutic option.
Our discovery that perturbations of microtubule PTMs can directly lead to neurodegeneration underpins the key importance of these modifications for neuronal functions and homeostasis.