The study of a rare familial form of Parkinson's disease led researchers of the University of Trento to describe a new pathological mechanism of the disease which, in the future, could be exploited for therapeutic purposes in non-genetic forms. Published in Brain*, the work was coordinated by Giovanni Piccoli, researcher of the Department of Cellular, Computational and Integrated Biology (Cibio), thanks to the Dulbecco Telethon Institute, the careers program of the Telethon Foundation.
Parkinson's disease is a slow but progressive neurodegenerative disorder that involves specific areas of the brain, the basal ganglia, responsible for movement and balance. Over time, affected patients show dopaminergic neuron degeneration in the basal ganglia, in parallel with the appearance of protein aggregates that have a toxic effect on the cells. To date, the molecular basis of the disease is still unknown and this has been a major obstacle to the development of effective drugs: at the moment, therapies based on L-dopa and dopamine agonist drugs only alleviate the symptoms, but do not cure the disease.
It is estimated that over 10 million people have Parkinson's disease worldwide. In most cases, the onset is sporadic, but there are also rare genetic familial forms that are caused by mutations in specific genes: by studying them, researchers have shed light on the mechanisms of the disease, that are still largely unknown. The group led by Piccoli studies a particular protein that is found in the brain and other tissues, LRRK2 which, in the G2019S mutation, is responsible for about 10 percent of the genetic forms of Parkinson's disease.
LRRK2 is involved in several cellular mechanisms, including the control of neuronal activity, and is a kinase, that is a protein that transfers a phosphate group to other molecules: this chemical reaction, called phosphorylation, is a fundamental mechanism used by proteins to regulate cellular programs. In the presence of the G2019S mutation, which is associated with the onset of familial forms of Parkinson's, there is an increase in the phosphorylation activity of LRRK2. Furthermore, studies conducted on autopsy material of patients and human neurons generated from pluripotent cells have shown that the G2019S mutation of LRRK2 induces cell death and the formation of protein aggregates. Among the target proteins of LRRK2 there is also NSF, an enzyme that is involved in the trafficking of vesicles: and it is precisely on this enzyme that Cibio researchers focused their work.
"We found that NSF, once phosphorylated by LRRK2, precipitates and forms protein aggregates which, in the long run, damage nerve cells not only in basal ganglia, but also in brain areas crucial for memory and learning, such as the cortex and the hippocampus – explained Francesca Pischedda and Maria Daniela Cirnaru, the researchers who conducted most of the experiments. The experimental results have in fact highlighted that, in the preclinical models of the LRRK2 G2019S mutation, NSF aggregation may be responsible for the motor and cognitive impairment typical of Parkinson's disease".
Given these results, the researchers then focused on how to promote the elimination of these toxic protein aggregates: the answer could lie in a process that in 2016 earned its discoverer the Nobel Prize for Medicine: autophagy. "Autophagy is a natural mechanism of the all cells for the removal of waste or harmful substances, like potentially toxic protein aggregates – explained Giovanni Piccoli. Studies on autophagy, since the work of Nobel laureate Yoshinori Ohsumi, have allowed us to understand this crucial phenomenon and to design drugs capable of stimulating it. In our case, we focused on a natural sugar, trehalose, which we tried to use to stimulate autophagy. Trehalose has been shown to be effective in reducing protein aggregation, cell death and motor and cognitive impairment in various preclinical models of the disease. The possibility of stimulating autophagy and therefore of removing the protein aggregates that damage neurons, in Parkinson's and also in other neurodegenerative diseases, is a promising therapeutic strategy".
The work of the University of Trento, carried out in collaboration with University College London, the University of Padova and CNR of Milan, confirms the key role of autophagy in diseases caused by protein aggregation. Further studies will be needed to transform these data into a real clinical opportunity.
* Francesca Pischedda, Maria Daniela Cirnaru, Luisa Ponzoni, Michele Sandre, Alice Biosa, Maria Perez Carrion, Oriano Marin, Michele Morari, Lifeng Pan, Elisa Greggio, Rina Bandopadhyay, Mariaelvina Sala and Giovanni Piccoli. "LRRK2 G2019S kinase activity triggers neurotoxic NSF aggregation". Brain, 2021 https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awab073...