Brain hereditary disease factor suspected

Jonasz Jeremiasz Weber, Rana Dilara Incebacak Eltemur, Priscila Pereira Sena, Huu Phuc Nguyen (from left) worked out the study together.
Credit: © Pengfei Qi

Similar to Alzheimer's, the hereditary disease Spinocerebellar Ataxia Type 17 (SCA17) leads to the demise of brain nerve cells and the premature death of those affected. The exact mechanisms of the disease are unknown, so there are no treatment approaches to date. Researchers of human genetics at the Ruhr University Bochum (RUB) around Dr. Jonasz Weber now suspects a class of protein-splitting enzymes, so-called calpaines, to contribute to the disease. In the model, the Calpaine was switched off to stop the course. The researchers report in the journal Cellular and Molecular Life Sciences.

Changed blueprint of a protein

Spinocerebellar ataxia type 17 (SCA17) is a rare, hereditary disease of the human brain. Due to the pathological change in a gene that contains the blueprint for a protein called TATA box-binding protein (TBP), the protein is formed in cells in a defective form. This also affects its function. "One consequence of this is that the protein forms detectable protein deposits in the brain and damages the nerve cells via molecular mechanisms that have not yet been fully elucidated," explains Jonasz Weber.

As a consequence, those affected by the disease develop symptoms such as movement disorders, seizures, impairment of mental performance as well as changes in nature and behavior, which are associated with the breakdown of tissues such as the cerebellum and brain stem.

Protein fragments are deposited

The molecular mechanisms that cause the disease have not yet been fully elucidated. One possible mechanism that could cause or at least influence the disease is the cleavage of the disease protein TBP by certain enzymes. This cleavage leads to even more harmful fragments of the TBP protein in the nerve cells. "Interestingly, previous studies have shown that these fission products also occur in the tissues of Alzheimer's patients and that they could also play a role in the course of the disease there," said Jonasz Weber.

Calcium balance is disturbed

The Bochum Human Genetics team led by Prof. Dr. Huu Phuc Nguyen has now been able to demonstrate that a special class of protein-splitting enzymes, the calpaine, can cause this division of TBP. "In addition, we were able to show that these enzymes are overactivated in cell and animal models of the SCA17," said Jonasz Weber. Since the activity of the calpaine is calcium-dependent, this finding suggests that genes that are involved in controlling the calcium balance of the cells may also be misregulated.

If the researchers inhibited the enzymes through pharmacological or genetic approaches, they were able to reduce the deposits of TBP and the production of the defective protein in the cell model. "Proof that Calpaine is involved in the SCA17 disease mechanism paves the way for further research," said Jonasz Weber. Further work could determine the relevance of this molecular process and find out whether and how it can be influenced. This could also result in therapeutic approaches for this disease. "This applies to both SCA17 and similar neurodegenerative diseases, in which it has already been demonstrated that calpaine plays a decisive role in pathogenesis," said the researcher.

Source/Credit: Ruhr University Bochum

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