THERE ARE genetic mutations that increase the risk of falling ill with Parkinson’s by 5 times, one of the most common neurodegenerative diseases, which affects about 400,000 people in our country alone. They are those that affect the GBA gene and are quite frequent: in Italy, about 14% of patients carry a GBA mutation, and even 20% of those with onset of the disease under the age of 50 are. One out of five patients has in practice an alteration of this gene, a reason that prompted the researchers of the National Parkinson’s Virtual Institute, one of the five created within the IRCCS Neuroscience and Neurorehabilitation National Network of the Ministry of Health, and 16 of the 30 IRCCS members of the Network, to conduct a survey enrolling 1,600 patients to better understand the role of these mutations in the disease. And to study this gene, an innovative method was developed, which combines selective amplification of the whole gene, sequencing with NGS (Next Generation Sequencing) technology, and targeted bioinformatics analysis. This technique will allow the identification of the most complex mutations with a very high sensitivity index, and with reduced costs and times compared to traditional technologies. In fact, within a year and a half, researchers expect to collect enough clinical and molecular data to explain the correlations between the genetic risk factor and the disease.
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The goal of the study
The GBA gene encodes the glucocerebrosidase enzyme active in lysosomes, that is a “digestive system” of the cell responsible for eliminating damaged organelles and toxic molecules: in practice, the “waste” to be disposed of. If this enzyme works poorly, neurons find it harder to free themselves from toxic substances, especially alpha-synuclein, the protein considered to be the main cause of Parkinson’s and which, accumulating in excess, causes neurons to degenerate. “We know with certainty that in patients with an altered copy of the GBA gene the risk of developing the disease is very high and we also think that it affects the severity of symptoms and the course of the disease. But the reason for this mechanism is to be understood and that is what we intend to do ”, he explains Pietro Cortellicoordinator of the National Parkinson Virtual Institute: “Through the Network, we plan to analyze the samples of a hundred patients for each IRCCS involved, and to collect clinical data so detailed as to allow us to make precise statistical correlations between the type of mutation identified and the more or less serious clinical picture of each patient “.
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A complicated gene
The record survey affects men and women with Parkinson’s, regardless of age of onset. To carry out the complete mutational analysis of the gene, the researchers will rely on an innovative protocol developed by a team of three researchers from the IRCCS Ca ‘Granda, Mondino and San Raffaele Hospital (Alessio Di Fonzo, Enza Maria Valente and Marco Morelli) , which will allow to analyze a considerable number of samples in a very fast and efficient way. “GBA is a very complicated gene to analyze, because it also has a pseudogene, that is a very similar sister gene that does not produce any protein and therefore has no importance for the purposes of our analysis – he underlines Enza Maria Valentefull professor of medical genetics at the Department of Molecular Medicine of the University of Pavia and head of the Neurogenetics Center of the IRCCS Mondino Foundation – It is precisely the pseudogene that can create many difficulties, because it ‘confuses the waters’ in the analysis process and often does not it is easy to understand if an identified mutation refers to the active gene or to the pseudogene “.
Developing protocols to selectively amplify and sequence the gene and not the pseudogene is therefore very complex. “Since even the new sequencing techniques had difficulty in distinguishing the variants between gene and pseudogene – continues the researcher – we decided to develop a protocol that would allow us to amplify a very large DNA fragment, specifically containing the active gene, and feed only this fragment to the sequencer. An action also supported by a bioinformatics analysis to thiswhich allows us to use NGS, take advantage of its speed, accuracy and cost-effectiveness, and confidently state that the identified mutations refer to the right gene ”.
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What is expected
The objectives to be achieved for the researchers are clear: to identify the carriers of mutations of this gene and to understand the correlations between the type of mutation and the clinical picture of the patient, to finally arrive at the development of personalized therapeutic strategies. “By June we aim to enter the clinical data in a common database – concludes Cortelli – by September to have the DNA samples of all the patients enrolled, and within the year to proceed with the genetic analysis”.
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