A team of scientists at the University of Granada has used a next-generation genetic sequencing method and a technique known as "Sanger sequencing" to conduct a detailed genetic screening of patients in Granada suffering from Parkinson's disease. They conducted the study in collaboration with the Movement Disorders Unit from the Virgen de las Nieves and San Cecilio hospitals, as well as with researchers from the Institute of Neurology at University College London (UCL).
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and the most common among disorders affecting movement. In spite of significant advances in recent years, scientists have so far been unable to decode the molecular mechanisms involved in its pathogenesis.
The scientific community is making great efforts to identify new gene candidates responsible for risk variants related to Parkinson's disease. The identification of these gene candidates may also help us to understand the possible pathogenic routes responsible for causing the disease and its different clinical subtypes.
Eleven pathogenic mutations
The UGR researchers identified eleven pathogenic mutations in the genes known as GBA, LRRK2, PARK2 and PINK1. One of the most interesting findings was the discovery of a new mutation (p.R32S) in the VPS35 gene in a patient with early-onset PD.
"In silico" bioinformatic simulation analyses, which are designed to predict the possible pathogenic effects of mutations through mathematical algorithms, estimated that the p.R32S mutation could be harmful. The alteration of amino acids was catalogued as harmful to the structure, stability and functioning of the protein codified by the VPS35 gene.
Nevertheless, the authors of the study note that "we have to interpret these findings with caution, as we cannot guarantee that the VPS35 p.R32S mutation is the cause of PD in the patient. The next step is to explore the presence of the mutation in healthy subjects and study the family-based segregation of this genetic variant. Furthermore, functional studies should be carried out in cellular models in order to test its pathogenicity."
The results of the study have been published in the journal Neurobiology of Aging and have significant clinical implications. The early symptoms of PD appear when the loss of dopaminergic neurons related to the aetiology of the disease reaches approximately 70%. The result is that the diagnosis is made many years after the neurodegenerative process begins. The genetic markers described in the study have a significant potential for bringing about earlier diagnoses of PD.
Identifying individuals at risk of developing PD
The genetic screening conducted by the UGR scientists makes it possible to identify individuals who bear these pathogenic mutations before motor symptoms of the disease appear. These individuals are therefore excellent candidates for clinical studies. Moreover, this type of analysis would help to identify true idiopathic PD and differentiate it from other movement disorders that exhibit similar symptoms. It would also help to stratify different clinical phenotypes which in the future could benefit from personalized medicine.