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Dr. Michele Lufino

Michele Lufino and Richard Wade-Martins

This research project has been co-funded by the following five associations (listed in alphabetical order): AISA (Italy), Ataxia UK, BabelFAmily,  FARA-Australasia, FARA USA.

Project summary in lay terms kindly supplied by Dr. Michele Lufino

Friedreich’s ataxia (FA) is a disease caused by a reduction in the levels of a protein called frataxin. What is known about the cause of FA is that the low levels of frataxin are due to a mutation in the gene coding for frataxin (FRDA), in particular a 3-base pair sequence (GAA) repeated up to 1700 times in the mutated FRDA gene. The way this mutation affects frataxin levels is not completely clear although several hypotheses have been described. Another subject that remains to be understood is the role of frataxin in the cell, since understanding its function will get us closer to a therapy. In our laboratory, we have generated cells that show the same effect of the GAA mutation on frataxin levels observed in Friedreich’s ataxia.

Furthermore these cells have been modified with a reporter gene, which flashes light whenever the FRDA gene is activated, making quantification of frataxin levels easy and rapid. Our aim is to use these cells to better understand the two main missing pieces of information, namely the pathological mechanism of the GAA mutation and most importantly the function of frataxin. First, we will study the direct effect of the GAA mutation on RNA synthesis, the first step involved in the cellular production of the protein frataxin and observe the way the GAA mutation affects this process. Second, we will investigate the role of frataxin by randomly mutating the genes of the cells we have generated, until we find mutations that affect the levels of frataxin. When this occurs, we will have found genes that are very likely to be implicated in frataxin cellular role, since their activity can influence frataxin levels.
This study will help us understand more about the mechanism through which the GAA mutation affects the levels of frataxin and also provide more information about the cellular role of this important protein. Both studies could help us develop novel therapeutic strategies.