UniPd-VIMM Research: progress against neurodegenerative diseases
16.01.2023
New research reveals that neurodegenerative diseases affect one in six people. Described as a large family of nervous system disorders, most forms of neurodegenerative diseases occur in adults with a more or less slow but progressively poor outlook.
Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's and motor neuron diseases manifest differently, ranging from cognitive impairment, psychiatric disorders, and other impairments characterized by the functional deterioration and ultimate loss of brain and spinal cord neurons.
Apart from clinical differences, neurodegenerative diseases share pathologies characterized by the accumulation of toxic proteins inside and outside neurons that manifest themselves after the age of 40 or 50. Moreover, neuronal cell death is associated with inflammation or activation of degeneration processes that lead to its self-destruction.
In most cases, pathologies are sporadic and not associated with mutations in specific genes but in some cases, they are associated with mutations in different genes. Only by studying genetic formation can we investigate the pathological processes in neurons.
The study published in Science Advances and coordinated by Maria Pennuto - University of Padua and VIMM - and conducted by researchers Diana Piol and Laura Tosatto, focuses on the study of Kennedy's disease, also known as spinal and bulbar muscular atrophy (SBMA), caused by the expansion of a polyglutamine tract in the gene encoding the androgen receptor.
The study reveals, "The antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded androgen receptor toxic gain-of-function. The mutation of the androgen receptor that causes the loss of those neurons is also investigated which allows us to carry out all voluntary movements, from the use of the facial muscles to swallowing to moving the legs and arms.”
Patients gradually move from using supports for walking to using wheelchairs due to fatigue and the inability to move. By studying how the androgen receptor works under normal conditions and in disease, researchers demonstrated that the mutated protein is modified by cellular factors that add or remove chemical groups. These modifications occur on the mutated receptor more strongly than on the normal receptor. The research team identified the factors responsible for these chemical changes and those that remove them. When factors are pharmacologically or genetically reduced there is an improvement in the functionality of the receptor, thus demonstrating the relevance of these discoveries in the context of Kennedy's disease. The research conducted between UniPd and VIMM included the collaboration of other laboratories in Italy and abroad.
The aim of the study was to identify new molecular targets and to increase our understanding of the field of neurodegenerative diseases.
Research project coordinator Maria Pennuto explains, “This study allows us to clarify that the mutated receptor undergoes the same changes as the normal receptor, but that the extent of these modifications is what changes, and are stronger in the case of the mutated receptor. This translates into non-optimal functioning of the receptor that fails to perform the functions it normally performs in neurons and muscle cells. Identifying the factors responsible for these changes will help achieve a better understanding of the pathological processes that occur in the patient and help us identify new therapeutic targets".
Pennuto's research project on Kennedy's disease began in 2013, when she received a grant of over 500,000 euros from the Autonomous Province of Trento, as part of the Telethon-Dulbecco Institute (DTI) careers programme, which allowed her to create an independent research group for the study of this pathology.
