In their Ataxia UK-funded research project, Dr Mariana Santos Moreda Graça and her team at the Institute for Molecular and Cell Biology (IBMC, Portugal) developed new cell models to help understand TTBK2 mutations and Spinocerebellar Ataxia Type 11 (SCA11).
SCA11 is a rare type of hereditary cerebellar ataxia with autosomal dominant inheritance (i.e. patients only need to inherit one faulty gene in order to have the disease). People with SCA11 show progressive movement incoordination and abnormal eye movements, due to degeneration of the cerebellum. The life expectancy of people with SCA11 is not affected, although the age of onset can range from 11 to 60 years old. Only four families with SCA11 have been reported to date.
All SCA11 patients carry a faulty (or mutated) gene, which is responsible for making a protein called TTBK2. TTBK2 is involved in many cellular processes, including those involved in other neurodegenerative diseases. Prior to this study, the group had identified a previously unknown mutation in the TTBK2 gene, found in a Portuguese family diagnosed with cerebellar ataxia. It appeared that this mutation has a similar effect on the TTKB2 protein as those mutations which cause SCA11.
In their project, the researchers developed a cell model which had the same mutation that they had previously identified in the patients. They also created cell models where parts of the TTBK2 gene had been deleted, which is expected to result in a shortened form of the protein.
These new cell models were created using a genetic technique called CRISPR/Cas9. In this technique, an enzyme called Cas9 is directed to sequences in the DNA, where it can act as a pair of ‘molecular scissors’, allowing parts of DNA to be added or removed.
These cell models will allow the researchers to characterise the effect of the mutation by comparing cells expressing mutated TTBK2, with cells expressing ‘healthy’ TTBK2. Their initial results have shown that the TTBK2 mutation they previously found in patients caused a decrease in the amount of TTBK2 protein. This indicated that the TTBK2 protein may be less stable, and that its function may be altered. The researchers are continuing with this research by looking into the proteins that TTBK2 interacts with, and which cellular mechanisms are affected in these models.
Learning more about this TTBK2 mutation will allow those that have it to be appropriately diagnosed. Moreover, this work may contribute to a better understanding of the cellular mechanisms underlying SCA11, which could open new perspectives on future treatments.
Date posted: 26/08/2021
