Huntington's disease is caused by a dominant mutation, which means that anyone who inherits it will develop the disease. Symptoms usually begin when people are in their 30s, and these include dementia and loss of motor control. Although we identified the gene decades ago, we have struggled to find a way to use this knowledge to improve patients' lives. The protein that is produced by the damaged gene is so similar to the normal version that targeting it is almost impossible.
But now, scientists in China have figured out a way to specifically get rid of damaged protein. They have identified molecules that can bind the damaged form of the protein to a system that cells use to target digestion and recycling proteins. Tests on mice and flies seem to indicate that this is enough to address many of the problems caused by the Huntington mutation.
Huntington's disease belongs to a class of genetic disorders caused by the expansion of DNA within the portion of a gene that encodes a protein. When translated into a protein, the DNA bases are read in three groups, each triplet encoding a different amino acid (or telling the cell to stop translating). If a protein needs the same amino acid several times in a row, the same triplet can be repeated multiple times.
In most cases this is not a problem. But the machine that copies the DNA when a cell splits, sometimes has problems with repetitive sequences, resulting in additional copies of the repetition after the cell splits. Over many cell divisions, these repeats can accumulate with dozens of the same three base codes in a row. They all encode the same amino acid, so if a protein can tolerate an expanded stretch of that amino acid, there is no problem.
However, some proteins cannot tolerate it. Huntington's disease protein is one of them, as well as a number of proteins associated with genetic ataxia. Although it is not clear what exactly defective form of the protein does at the biochemical level, it is clearly toxic to nerve cells. Over time, defective proteins accumulate in aggregates, interfering with nerve cell functions and ultimately killing them. Protein is also found in other cells and is critical for early development, but the cause of the worst problems is the death of nerve cells.
All these characteristics make the disease incredibly difficult to target. The defective protein is similar enough to the normal one that you can't just target it ̵
Finding a Linker
Researchers behind the new work have decided that there may be an easier way to get rid of a defective protein version. Although multiple stretching of the amino acid does not have an obvious function that could be inhibited, it may be possible to find a small molecule that has been attached specifically to it. And if they have that, they could use the molecule to manipulate the fate of the protein.
To do this, the team created an array of about 3400 chemicals and then identified those that adhere to the multiple amino acids of the defective protein. At the same time, they check the same chemicals as those that have stuck to a protein involved in a process called autophagy. Autophagy is the process by which cells absorb old or damaged components in order to recycle them into raw materials for further growth. Binding of a protein to an autophagic component may allow the system to absorb the high frequency protein.
They extracted two chemicals that seemed to adhere to the two proteins. They tested these and showed that they specifically interact with the defective version of the Huntington gene, not the normal one (they also confirmed that it does not adhere to the protein by trying a few random ones). And, as hoped, when given to cultured nerve cells, the chemicals reduce the levels of the defective protein rather than the normal one.
But chemicals that leak out of the screen have been known to interact with other key proteins in a cell (such as the Raf growth regulator). So to get something specific about the Huntington protein, the researchers then looked at the structures of the two successful chemicals and identified a number of additional chemicals that share some of the key characteristics of the two. They identified two additional chemicals that could be targeted for Huntington's defective protein for destruction, but were more specific to it. They have the same effects as the original two, providing evidence that the decreased protein levels in Huntington are due to its transfer to the autophagy system.
With all its promise, researchers have moved to animal testing, showing that it works with flies that have a mutant version of the equivalent gene. They then switched to mice that were designed to carry a mutation similar to that seen in humans. Injections of the drug into mice showed that both chemicals could reach the brain and reduce protein levels by over 20%. Although not completely eliminated, it was sufficient to alleviate the symptoms commonly seen in mice carrying this mutation.
As a final test, researchers made stem cells from Huntington's patients, turned them into neurons, and tested the chemicals there. Chemicals acted and did not cause additional toxicity. The tests also confirm that the chemicals have very little effect on other proteins in the cell, indicating that they do not cause an overall increase in autophagy.
As a final test, the researchers tested it on the mutant ataxia protein. As mentioned above, several forms of ataxia are caused by the expansion of the same amino acid, which is duplicated in the Huntington's disease gene, and thus may be subject to the same type of interaction with these two chemicals. Tests show that they did, reducing the levels of these mutant proteins.
This is very far from effective treatment as there are no clinical tests to date. But this is probably less important than the fact that people have figured out a way to target it potentially with a small molecule drug that can cross the blood-brain barrier. For all its limitations, small molecule drugs have a number of huge benefits: they can be taken as pills, they are stable at room temperature, and we have a very good understanding of the safety issues associated with their mass production. .
Even if these particular molecules do not work, the approach itself may lead to something it does.
Nature 2019. DOI: 10.1038 / s41586-019 -1722-1 (For DOI).