UniTrento, neuronal regeneration: the perspective changes from CIBIO

This time, the research did not address a specific disease, but focused on the mechanism of neuron maturation . On how maturation is started and increased. Also because this may be at the center of a series of motor neuron diseases, the most prevalent and important are amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), diseases affecting the nerves responsible for the muscular control, causing progressive paralysis

By attempting an original approach to the problem, researchers at the CIBIO Laboratory for Translational Genomics – Center for Integrated Biology, led by Alessandro Quattrone, reversed the more clbadical perspective. Instead of starting from the causes of motor neuron degeneration, they focused on the factors of maturation. "The idea is that stimulating maturation in already mature neurons could counteract degeneration, regardless of the specific lesions that cause it, and implement the process that neurologists would have wanted for their patients for decades: neuronal regeneration" .

The study, the result of international collaboration, lasted five years and led to unexpected results. They say: "We focused on a factor called HuD, already known for its ability to induce nervous development.Analysis of all the genes controlled by this factor showed that it acts on the group of those that induce cell growth by stimulating the machinery of protein synthesis.The most interesting thing was to see that the factor acts independently of the processes we already know to induce this fundamental phenomenon.This is a kind of "overdrive" , which gives the machine much better performance than the base engine, but the big news came later, when we observed that the overdrive factor is, in the motoneurons, "chained", deleted by another molecule called Y3.The close badociation between HuD and Y3 prevents HuD from functioning at high levels in motor neurons. "

Quattrone emphasizes: "We have found, in other words, that a protein that is very potent in the production of innervation during the early stages of development is then repressed in the mature neuron," glued to another molecule that inhibits it. When we try to detach him from the latter, his power manifests itself with a force and a precision that struck us. To better understand, we can go back to the famous discovery of Rita Levi Montalcini, that of NGF, the first factor capable of inducing the maturation of neurons from the outside. Unfortunately, due to various problems, we have not managed to make it a medicine for nearly half a century. Now we find this other protein, which is directly inside the neurons, is asleep, and its awakening has an effect comparable to that of NGF. So we must find a way to eliminate the inhibition in patients with motor neuron diseases because we expect that they stimulate regeneration. And its field of application may not be limited to the neurodegenerative area, since the tumors of the nervous system are from a certain point of view of cell maturation blocks. "

The results of the study were published in the American journal" Molecular Cell ". They are the fruit of a coordinated work with three other laboratories of CIBIO, the Institute of Biophysics of CNR Trento, Institute of Molecular Medicine of the University Martin Luther of Halle, the Wellcome Center for Cell Biology and the School of Computer Science. University of Edinburgh. It was made possible by the AxonomiX Big Project of the Autonomous Province of Trento and the Cbada di Risparmio Foundation of Trento and Rovereto and has four main authors: Daniele Peroni, Paola Zuccotti, Toma Tebaldi, all at CIBIO in the years of the project, and Marcel Kohn

Tebaldi, who is now working as a researcher at the Yale School of Medicine Cancer Center, adds: "The molecule that blocks the neural maturation factor, Y3, belongs to a very clbad of molecules. common in the genome, but no one knew the function and that it was considered a garbage bin.On the contrary, they have fundamental factors to understand the great complexity of life.It is fascinating to think that Y3 is a paradigmatic example of the hidden potential in the dark matter of the cell. "

The team concludes:" The overdrive repressed in motor neurons opens a new path in the fight against terrible diseases and unfortunately without cure. This discovery, the result of fundamental research, indeed gives rise to the possibility of new therapeutic applications, which must however find a way to detach the two factors and to release the potential of the inhibited. Another topic of interest is to understand if inhibition is absent, as can be expected, in organisms, such as fish and some amphibians, known to be able to regenerate nerves very effectively, which unfortunately does not happen in our species "