A research group led by Dr. Dáša Bohačiaková from the Institute of Histology and Embryology of the Masaryk University Faculty of Medicine has identified a key genetic mutation influencing the onset and progression of Alzheimer’s disease, now published by the prestigious journal Proceedings of the National Academy of Sciences.
The study was carried out in international cooperation, especially with Danish colleagues from Aarhus University.
The emergence of the so-called familial form of Alzheimer’s disease, which appears at a younger age than the sporadic form, is caused by genetic factors. Recently, there has been increasing evidence that, in addition to “traditional” genes such as APP, PSEN1 and PSEN2, the SORL1 gene also plays a role in the development of familial Alzheimer’s disease. Its mutations can disrupt the production and function of the SORLA protein and thus negatively affect processes in brain cells, increasing the risk of developing Alzheimer’s disease. Research by Brno scientists has now confirmed this role.
Of the more than 500 variants of the gene, the study specifically focused on one designated p.Y1816C. This variant was found in three families from Italy, the Netherlands and Spain, where the carriers suffered from an early form of Alzheimer’s disease.
“We characterised the p.Y1816C mutation and rigorously described its function and how it affects the function of human neurons created from stem cells,” explained Bohačiaková. “Under normal circumstances, the SORLA protein forms the dimers necessary for the proper transport of materials inside the cell. However, the given mutation prevents this process. When the mutation existed, the newly formed neurons showed characteristic signs of Alzheimer’s disease. The study thus provides genetic and functional evidence that the given variant of the SORL1 gene is the causative factor of the disease.”
The research contributes to a better understanding of the genetic factors and molecular mechanisms of Alzheimer’s disease. The identification and study of specific genetic variants affecting its development may in the future lead to earlier and better diagnosis, as well as more effective treatments, which could significantly improve the quality of life of patients. Furthermore, the results of the study may apply to other diseases; other studies indicate that the SORL1 gene also affects the development of other neurodegenerative diseases, including Parkinson’s disease.
In addition, the Brno study shows that the defects caused by the p.Y1816C mutation can be at least partially corrected by modifying the relevant protein receptor, thus further underlining the importance of early diagnosis.
Dr. Bohačiaková suggests another direction of research and the possibility of personalised treatment being introduced into the field of neurology. “If we know that a specific gene mutation has a causative effect on the onset of Alzheimer’s disease and we also know that there is a repeated occurrence of the disease in the family, we will be able to focus on this mutation in time and refine genetic screening and diagnosis. The study of specific gene variants can also potentially lead to the development of new therapeutic approaches specifically targeting these mutations,” she said.
