Researchers at the Brain Mind Institute of the École Polytechnique Fédérale de Lausanne (EPFL) say they identified an enzyme that can open the door to developing a new route of treatment for Huntington’s Disease.

The kinase enzyme, called TBK1, plays a central role in regulating the degradation and clearance of the huntingtin protein and introduces chemical modifications that block its aggregation, according to the team working in the lab of Hilal Lashuel, PhD.

Their study “TBK1 phosphorylates mutant Huntingtin and suppresses its aggregation and toxicity in Huntington’s disease models” appears in The EMBO Journal.

Our work shows that TBK1-mediated increase in phosphorylation and/or promoting mutant huntingtin autophagic clearance represent viable therapeutic strategies for the treatment of Huntington's Disease," says Ramanath Hegde, who led the study.

Progressive and aggressively debilitating brain disorder

Huntington disease is a progressive and aggressively debilitating brain disorder that causes uncontrolled movements, psychological problems, and loss of cognition. It is caused by a mutation in the gene that encodes the protein huntingtin, causing it to build an abnormally long tail of the amino acid glutamine. This tail prevents huntingtin from folding properly and as a result it aggregates inside neurons of the brain, and eventually kills them.

Previous studies have shown that artificially adding phosphate groups to huntingtin can stop it from aggregating and causing Huntington's disease. "However, to explore the therapeutic potential of phosphorylation, we needed to identify the natural kinases that do the job inside the cell," says Lashuel. "After screening hundreds of kinases, we were excited to identify TBK1, because it did the job with high specificity and efficiency."

The researchers found that, when TBK1 adds a phosphate group anywhere in the first 17 amino acids of huntingtin, it inhibits its ability to aggregate. This was the case for both the normal and mutated versions of huntingtin.

In addition, increasing TBK1 levels in cells leads to over-phosphorylation of a specific amino acid (a serine) in the huntingtin chain. This stabilizes the protein and stops it from aggregating.
Finally, TBK1 was also found to signal the cell to degrade and clean out huntingtin before it aggregates. This lowers overall huntingtin levels, which results in reducing aggregate formation inside the cell.

An animal model of Huntington's Disease

Encouraged by their findings, the scientists then moved onto an animal model of Huntington's Disease: the worm C. elegans. What they found corroborated their previous data: Over-expressing the TBK1 kinase protected against mutant huntingtin toxicity in the worm, preventing the development of Huntington's Disease. The researchers got similar results in cultured neurons.

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