
Using an in vitro kinome screen, the lab of Hilal Lashuel at EPFL identified a novel kinase (TBK1) that Phosphorylates the huntingtin protein at S13 and S16 and showed that it plays a vital role in regulating its aggregation, clearance, and toxicity. In cells, TBK1 phosphorylates HTT at S13, leads to the reduction of mutant HTT aggregates in cells and C. elegans, and protects against HTT toxicity via a mechanism that involve increasing HTT S13 phosphorylation and/or promoting the clearance of soluble HTT via autophagy.
Credit: R.N. Hegde and H. Lashuel (EPFL)
Scientists at EPFL’s Brain Mind Institute have identified an enzyme that can play a central role in developing a new route of treatment for Huntington’s Disease.
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.
Huntington’s affects hundreds of thousands of people in the world, and as an “autosomal dominant” disease, a person only needs one copy of the mutant huntingtin gene to develop the disease. Scientists in both academia and industry are exploring different approaches to tackle the disease. The most popular strategy is to lower the levels of huntingtin or to inhibit its aggregation – or a combination of both. The way to do this is to either “silence” the huntingtin gene or to activate cellular mechanisms that promote the degradation of the protein itself.
Now, scientists at the lab of Professor Hilal Lashuel at EPFL have identified a new enzyme that does both. The 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. “We believe that this represents a viable target for the development of possible treatment of Huntington’s disease,” says Lashuel.
The TBK1 enzyme is a “kinase”. In the cell, kinases are enzymes that add phosphate groups to various biomolecules like proteins or DNA. In the world of the cell, phosphate groups are energy-carriers, so adding one essentially “turns on” the receiving molecule.
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.
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.
Using an in vitro kinome screen, the lab of Hilal Lashuel at EPFL identified a novel kinase (TBK1) that Phosphorylates the huntingtin protein at S13 and S16 and showed that it plays a vital role in regulating its aggregation, clearance, and toxicity. In cells, TBK1 phosphorylates HTT at S13, leads to the reduction of mutant HTT aggregates in cells and C. elegans, and protects against HTT toxicity via a mechanism that involve increasing HTT S13 phosphorylation and/or promoting the clearance of soluble HTT via autophagy. Credit: R.N. Hegde and H. Lashuel (EPFL)
“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.
“We are very excited about these findings,” says Lashuel. “TBK1 has also been shown to regulate the clearance and degradation of proteins implicated in other neurodegenerative diseases. Mutations in TBK1 have also recently been linked to ALS and result in impaired autophagy, which leads to the accumulation of aggregates. Our goal is to find small molecules or drug pathways and to develop these for multiple neurodegenerative diseases.”
The Latest Updates from Bing News & Google News
Go deeper with Bing News on:
Huntington’s Disease
- Thousands of kidney disease patients set to benefit from £1-a-dose diabetes drug which can reduce the need for dialysis and a transplant
Kidney disease is usually triggered by the damage caused by another illness, such as type 1 and type 2 diabetes or high blood pressure.
- Doctors discover many inflammatory bowel disease patients screen positive for malnutrition
Eating food and absorbing its nutrients is an everyday occurrence, but this normal activity can look different for someone who suffers from inflammatory bowel disease. IBD, which includes Crohn's ...
- Three dead, two hospitalized after outbreak of Rocky Mountain spotted fever as CDC warns anyone with symptoms of the tickborne disease to start treatment without waiting for ...
Three people have died and two people have been hospitalized following an outbreak of Rocky Mountain spotted fever.
- New cause of diabetes discovered, offering potential target for new classes of drugs to treat the disease
Researchers have identified an enzyme that blocks insulin produced in the body -- a discovery that could provide a new target to treat diabetes. The study focuses on nitric oxide, a compound that ...
- Getting through the holidays with celiac disease
As I prepared for my women's group Christmas cookie exchange, I realized how tough this season might be for someone with celiac disease. This condition can cause immense damage to the intestines when ...
Go deeper with Google Headlines on:
Huntington’s Disease
[google_news title=”” keyword=”Huntington’s Disease” num_posts=”5″ blurb_length=”0″ show_thumb=”left”]
Go deeper with Bing News on:
Treatment for Huntington’s Disease
- Thousands of kidney disease patients set to benefit from £1-a-dose diabetes drug which can reduce the need for dialysis and a transplant
Kidney disease is usually triggered by the damage caused by another illness, such as type 1 and type 2 diabetes or high blood pressure.
- Three dead, two hospitalized after outbreak of Rocky Mountain spotted fever as CDC warns anyone with symptoms of the tickborne disease to start treatment without waiting for ...
Three people have died and two people have been hospitalized following an outbreak of Rocky Mountain spotted fever.
- New cause of diabetes discovered, offering potential target for new classes of drugs to treat the disease
Researchers have identified an enzyme that blocks insulin produced in the body -- a discovery that could provide a new target to treat diabetes. The study focuses on nitric oxide, a compound that ...
- New insights into how anti-obesity drugs could help prevent kidney disease
Data from Australian researchers could partly explain why a trial of a new drug for diabetes, was recently halted because it was found to be so effective.
- Study identifies new target for fatty liver disease treatment
The global rise in obesity and diabetes is leading to an epidemic in fatty liver disease affecting 20-30 per cent of the world's population.
Go deeper with Google Headlines on:
Treatment for Huntington’s Disease
[google_news title=”” keyword=”treatment for Huntington’s Disease” num_posts=”5″ blurb_length=”0″ show_thumb=”left”]