They discover the cause of a rare genetic disease, a key finding for future therapies

The disease Progressive neurological disease or spinocerebellar ataxia 4 (SCA4) is a rare pathology that begins with difficulties walking and maintaining balance, symptoms that worsen over time. Although it can start in adolescence, It usually manifests itself at forty or fifty years of age, and there is no cure.

Until now, the exact cause was unknown, but an international study led by University of Utah neurologists Stefan Pulst and K. Pattie Figueroa has just conclusively identified the genetic cause of SCA4, a finding that opens the door to future treatments.

The details of the research were published this Monday in the journal ‘Nature Genetics’.

SCA4 was known to be a genetic disease caused by a gene in a specific region of a chromosome, but the area turned out to be extraordinarily difficult for researchers to analyze.

To identify the change caused by SCA4, the team led by Figueroa and Pulst compared the DNA of affected and unaffected people from several families in Utah and found that, in patients with SCA4, a section of a gene called ZFHX3 is much more longer than it should be, since it contains an extra long chain of repetitive DNA.

Isolated human cells that have the extra-long version of ZFHX3 show signs of disease: They don’t seem able to recycle proteins as well as they should, and some of them contain clumps of stuck proteins.

“This mutation is a toxic expanded repeat and we think it really jams the way a cell deals with unfolded or misfolded proteins. Healthy cells need to constantly break down non-functional proteins”explains Pulst.

Using cells from patients with SCA4, the group showed that the mutation causing SCA4 jams the cells’ protein recycling machinery, which could poison nerve cells.

Hope for the future

Interestingly, something similar seems to occur in another form of ataxia, SCA2, which also interferes with protein recycling. Researchers are currently testing a potential therapy for SCA2 in clinical trials, and the similarities between the two conditions raise the possibility that the treatment could benefit patients with SCA4 as well.

Discovering the genetic change that causes SCA4 is essential to developing better treatments.

“The only step to truly improve the lives of patients with hereditary disease is to find out what the primary cause is. “We can now attack the effects of this mutation potentially at multiple levels,” says Pulst.

But although treatments will take a long time to develop, simply knowing the cause of the disease can be incredibly valuable for families affected by SCA4, because they can know whether or not they have the genetic change causing the disease, which can help them. to make vital decisions such as family planning.

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