Approximately 5% of Parkinson’s patients carry dominant mutations in the TMEM175 gene; these mutations would be implicated in a form of the disease that occurs after 50 years of age. This is what emerges from a research born from the collaboration between Irccs Neuromed of Pozzilli (Iss) and the ‘Adriano Buzzati Traverso’ Institute of Genetics and Biophysics of the National Research Council of Naples (Cnr-Igb), financed by the Ministry of Health and whose results were published in the scientific journal Molecular Neurobiology.
The protein produced by the gene studied – explains a note – is essential for the regulation of acidity within lysosomes, cellular organelles that act as real ‘cell scavengers’. In fact, the decomposition of cellular components that are no longer useful or of harmful elements takes place inside them, for example proteins folded incorrectly or worn organelles. The process, called autophagy, keeps cells healthy by constantly renewing their components. When lysosomes don’t work properly, as can happen if their acidity is not the right one, there is an accumulation of real waste, which can be the basis of degenerative pathologies.
Like all genes, TMEM175 can also present different variants. It is on this aspect that the study focused. In particular, the researchers studied both human tissues and animal models, examining the different gene variants as well as the process of gene expression (the transcription of genetic information into proteins). TMEM175 was particularly expressed in dopaminergic neurons of the Substantia Nigra, precisely those whose degeneration is the main cause of Parkinson’s, and in cortical microglia cells, which may be involved in neuroinflammatory processes. This is the largest genetic study carried out on Italian patients suffering from Parkinson’s disease – continues the note – using latest generation sequencing methods.
“We were able to identify a large number of pathogenic mutations in the TMEM175 gene that alter the functionality of the lysosomal potassium channel and prevent the correct functioning of lysosomes”, says Nicole Piera Palomba, researcher in the Cnr laboratory at Irccs Neuromed, first author of the work .
An important aspect of the study was being able to analyze a large number of cells deriving from patients affected by mutations in that gene. “The study carried out on the fibroblasts of Parkinson’s patients – explains Giorgio Fortunato, PhD student at the ‘Buzzati-Traverso’ Institute of Genetics and Biophysics, co-first author of the study – allowed us to demonstrate that the mutations in TMEM175 alter both the autophagy and the response to endoplasmic reticulum stress (involved in the synthesis and transport of cellular proteins and lipids, ed). They are important factors for the functionality of the dopaminergic system, the degeneration of which leads to the development of the pathology”.
“These results – concludes Teresa Esposito, researcher at the ‘Buzzati-Traverso’ Institute and head of the Cnr Laboratory at Neuromed – can have an important impact on the molecular diagnostics of Parkinson’s disease, by early identifying people at high risk. If we consider that in Italy there are at least 200,000 people affected by this pathology, the molecular analysis of the TMEM175 gene, mutated in 5% of patients, should always be considered in the diagnostic protocols of Parkinson’s disease Other studies will naturally be needed, on the one hand to increase the number of diagnosable patients, on the other to understand and develop potential therapeutic approaches, first of all those based on pharmacological developments and regenerative medicine”.
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