The excess of tubulin polyglutamylation perturbs transport in primary hippocampal neurons and causes extensive neurodegeneration in mice and humans.
Researchers from Carsten Janke’s group from Institut Curie have recently published two articles of important relevance in the field of Neurobiology.
Neurobiology is the branch of biology, which explores neurons, these tentacle cells also known as nerve cells, which are the primary components of our Nervous System.
A typical neuron1 consists of a cell body, dendrites and an axon2 (see images 1 and 3) 1,4. Most neurons receive signals via the dendrites and send out signals down the axon. However, to allow the spreading of those signals, materials have to be transported to the right place at the right time in the axons.
“Scientists are amazed that microscopic materials can be transported more than several feet along one neuron that goes from the spinal cord to the foot. This is equivalent scale to a person carrying a package walking along the wall of China” 3.
Neuronal cells have to transport mitochondria, vesicles and other materials from one side to the other for their correct functionality. This means from the neuronal cell body to the end of the axon (synaptic terminal) and vice versa. In order to do this, neurons use microtubules as highways along the vast length of their axon.
Image 1, 2 and 3. From top to bottom: 1A typical neuronal cell with its nucleus in pink and axon and dendrites in blue. 3Great Wall of China, represents the analogy with axons of some neurons. Those axons are so long, that the material travelling along them can be compared to the transport of a package along the Great Wall of China. 3Main parts of a neuron: cell body, dendrites and axon.
Many neurodegenerative diseases can be related to the dysfunction of microtubules. Therefore, studying the mechanisms that can influence and alter the properties and functions of microtubules is of important interest since they could play a role in neuronal disorders.
One of the mechanisms that alter the properties of microtubules, and how things move on them, are “tubulin posttranslational modifications”. But, what does this exactly mean? And what is tubulin? Let’s start answering the second question! In cells, there are big structures, polymers, built from small elements, or monomers, like a big structure built from small Lego bricks. Microtubules are one such polymer, and their Lego bricks are the tubulin proteins. Meaning one tubulin after another tubulin, after another tubulin, after another tubulin… form a microtubule! (see figure 4) 5.
Figure 4. The analogy between microtubules and a Lego structure. Lego blocks assembled as an example of how monomers (a single Lego blocks or tubulin) form a polymer (a Lego structure or a microtubule). Left image: a Lego structure, right image: a 3D model of a microtubule.
Regarding the first question – what are posttranslational modifications? – we need to imagine a factory chain. In this factory, the manufacturers produce tubulin, and, as in every factory, the products undergo several steps in the whole production chain. After the first step of protein production, tubulin assembles into microtubules, which then undergo some changes, meaning that at the end of its assembly line, microtubules are modified (see figure 5) 6.
Figure 5. Image adapted to show the different steps of the maturation of the protein tubulin. In this case the posttranslational modification that is common on neuronal microtubules is named polyglutamylation.
The scientists of this discovery, focused particularly in a modification named “polyglutamylation”, that consists in the addition of glutamate groups to the tubulins forming the microtubules.
In general, as many things in life, balance is good and excess of something can have bad consequences. In this study, scientists, using mouse models, have discovered how neurodegeneration occurs as a direct cause of an excess of polyglutamylation. In other words, when microtubules get too much of these glutamate groups (in red in the diagram), they change they properties in the axons of neurons, disturbing the transport and therefore leading to the degeneration of a variety of neurons in the central nervous system (see figure 6)7.
Figure 6. Image showing the analogy between transport of materials on microtubules in cells and traffic of cars on roads. Balanced microtubule polyglutamylation in neurons would be the case of good car traffic. However, the excess of polyglutamylation provokes a disruption in the traffic and leads to neurodegeneration in neurons.
Importantly in this research, the authors Magiera and collaborators were able to reverse the neurodegeneration by inhibiting the process of polyglutamylation, a discovery holding the promise that specific inhibitors could be used in the near future as potential therapeutic agents to treat disabling and often, fatal neurodegeneration, for which so far, no treatment is available.
Their second article – Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration – in which they analyzed 13 patients, makes the important discovery that dysregulated microtubule polyglutamylation is also detrimental to human neurons. This gives more value to their discovery in mice and entails more strongly this “posttranslational modification” as a potential target for drug development for human neurodegenerative disorders.