What is Huntington's disease? Why is it a world medical problem?

Li Xiaojiang | Professor of Guangdong-Hong Kong-Macao Central Nervous System Regeneration Research Institute, Jinan University

What is Huntington's disease? How big is the patient population?

Huntington's disease is a neurodegenerative disease.

It is a hereditary neurodegenerative disease that can be passed down from one generation to the next, and is mainly caused by a single gene mutation. Its gene mutation involves a string of nucleotide sequences, which is an increase in the number of CAG sequence repeats. Most people carry this sequence, but the normal sequence is less than 36; once it exceeds 36, it may cause Huntington's disease.

The typical symptom of Huntington's disease is the selective death of nerve cells. Nerve cell death mainly occurs in the striatum of the brain, and the striatum is mainly responsible for controlling the body's movement coordination, so patients will experience chorea.

In Chinese, Huntington's disease is also called chorea. The disease develops with age - the mutation starts at birth, but symptoms, including nerve cell death, usually occur in middle or late life. Most patients develop Huntington's disease in middle or late life.

Therefore, this disease has many similarities with other neurodegenerative diseases. For example, Alzheimer's disease and Parkinson's disease, which we are familiar with, belong to this category of diseases. They are all neurodegenerative diseases that occur with age. Its pathological changes are due to the precipitation of some protein aggregates, which are mainly due to the conformational changes of mutant proteins produced by mutated genes. If they are precipitated in the nerve cells of the brain, they may cause the death of nerve cells.

So from this point of view, if the study of Huntington's disease can find a treatment, it will be of great significance for the pathological exploration and treatment of other neuronal cell death caused by the precipitation of related mutant proteins.

From a group perspective, the exact number of people with Huntington's disease is still unclear. In Western countries, it is generally about one in 50,000, but considering the large population of Chinese (more than 1.4 billion), the actual number is estimated to be higher than in many other Western countries. I know that in some hospitals, the number of Huntington's patients is 500 - just in one hospital. That is to say, if the patients are counted, the number of cases collected in one hospital has reached 500.

From this disease, we can see that since the Chinese population is relatively large, there are actually more patients in the national population.

Why do sports mental disorders occur?

Many theories have been generated from the study of many molecular mechanisms. It should be said that Huntington's disease may actually affect the functions of many cells, but which one is the most important has not yet been determined.

However, there is a relatively clear conclusion, that is, the gene that causes Huntington's disease can generate a protein with a total length of about 3,000 amino acid residues. This long protein is not very toxic. Only when the protein is hydrolyzed, it forms small fragments, and these small fragments carry the information of the mutation, that is, the lengthened polyglutamine polypeptide sequence translated by the growth of the CAG repeat sequence, and the growth of this polypeptide sequence will cause the toxicity of the protein (and thus cause disease).

So from this point of view, it is clear to everyone that the real pathogenic factor of this disease is a truncated protein with extended polyglutamine left after proteolysis. So, since this protein can cause toxicity, where is its toxicity manifested? First, it can enter the cell nucleus and then affect gene expression.

Under normal circumstances, the full-length protein is mainly in the cytoplasm. However, after being cut, the truncated protein can go to the nucleus, the axons of the nerves, and the synapses, and affect the functions of these structures. For example, some changes in signal transduction are the effects of molecules on the release of neurotransmitters. It may also affect the corresponding nerve conduction due to synaptic changes, including functions such as the transport of substances (neurotransmitters, etc.).

There are many theories to explain this disease, but they are all basically attributed to mutant proteins, which carry a string of extended glutamine polymers. The extended polyglutamine can cause the precipitation of truncated proteins and conformational changes, and non-specific and abnormal binding with other proteins, affecting the function of these proteins. It can be seen that the relevant molecular mechanisms are still relatively complex.

Limb movement is controlled by many nerve cells, including the spinal motor neurons we are familiar with, which are the most typical type. In addition, of course, our cerebral cortex, various neural networks and neural circuits also play an important role in controlling limb movement.

The toxicity of Huntington's disease (virus) protein is mainly to nerve cells. If an autopsy is performed on a deceased patient, it can be seen that many such protein aggregations and cell deaths occur in nerve cells and tissues.

The toxic protein also has a more important role, which is to selectively affect the function of nerve cells in the striatum. As I just said, the nerve cells in the striatum are very important for the coordination of our limb movements, so when it kills these nerve cells, the patient's motor symptoms are very typical. This is one of the earliest obvious symptoms.

In addition, it actually affects the cerebral cortex or other different parts, but it has a greater impact on the motor neurons of the striatum. Therefore, patients show symptoms of chorea or incoordination of movement.

Do symptoms vary across the different stages of Huntington's disease?

The most common symptoms of Huntington's disease are the motor symptoms I just mentioned. In addition, there are some other symptoms. For example, loss of memory function - a bit like Alzheimer's disease. There are also mental symptoms - these patients generally have symptoms similar to mental illness. There are also emotional symptoms. These are all accompanied. However, the most important symptoms are still motor symptoms. Because of the motor symptoms, in practice, the patient's ability to take care of himself is significantly affected.

I don't know if you've ever seen a Huntington's patient. He sits there and moves involuntarily, and can't walk very well, and these problems seriously affect his ability to live. These are some of the most obvious symptoms. In addition, it is similar to many neurological diseases, such as psychotic symptoms, memory loss, reduced learning ability, and many other aspects of function will be affected.

Is Huntington's disease related to age and gender? Is it hereditary?

(This disease is not related to gender) very much. Once the gene mutation is present, both men and women will develop the disease, and the chance is the same. As for age, as I just said, individuals carrying this gene do not show symptoms when they are born, and usually only develop the disease when they reach a certain age (middle or late age).

There are also cases of young, juvenile onset disease, but these are rare. This condition occurs when the CAG repeat sequence in the gene mutation is excessively long, causing symptoms in adolescence.

Huntington's disease is very hereditary. As long as one parent carries the gene, it is likely to be passed on to the next generation. So about 50% of the family members may carry the gene. If you carry the gene, you will sooner or later develop symptoms of the disease. So it is a very typical single gene mutation disease, and it is also a disease with a very close genetic correlation. It is also a very typical case for studying hereditary neurodegenerative diseases.

What are the current treatments for Huntington's disease? How can Huntington's disease be prevented?

Many people have tried drugs such as small molecule compounds, and a lot of work has been done on small animal models, but in fact, almost none of them have been successful in patients.

Based on what I just said, the Huntington's disease gene is the product of a single gene mutation. A mutated gene will also produce a mutated protein. The best treatment is to prevent the mutated gene from translating into protein at the source. In this sense, it is to inhibit the RNA expression of the disease-causing gene and prevent the protein from being produced.

From this perspective, many preclinical experiments have been done, using what we call Antisense Oligo technology to treat such diseases. This method has been very successful in mouse models, but it has also been used in patients and reported in clinical trials, but it has not been successful in clinical operations, and people are still looking for other different methods.

There is a good method - gene therapy, which may be more effective to specifically inhibit protein expression (RNA translation expression), that is, to directly repair the gene or remove the mutated gene. This method is more credible, and it is also what we have been doing recently, trying to use this method to see if it can treat Huntington's disease.

There is still no effective treatment for this disease, but it can be detected early through early diagnosis. Although there is no good treatment for this disease, it is a genetic disease. As long as you know that your family members or one of your parents has this disease or carries this mutated gene, generally speaking, it is easy to evaluate with the current genetic diagnosis method. But there are some phenomena involved, that is, some patients know that there is Huntington's disease in their family, but they are unwilling to get a diagnosis, because even if they are diagnosed, there is no ready-made effective treatment. If they cannot be treated, they are unwilling to bear this pressure; if they are diagnosed, they will also feel that it may have a great impact on their future life and work.

Therefore, at present, there is no way to prevent it. In fact, if the carrier of this mutated gene wants to give birth to the next generation, it is very necessary to first check the embryo or germ cells to determine whether it carries the disease-causing gene. I just mentioned a 50% chance, so this can prevent the 50% incidence rate and achieve the effect of prevention. In practical application, this is a measure during the reproductive or pregnancy stage, and this diagnosis should be done.

Where is the breakthrough in conquering Huntington's disease?

This disease is a neurodegenerative disease caused by a single gene mutation, so its research importance is no less than that of Parkinson's disease and Alzheimer's disease.

Why? Its pathogenesis is very clear, and a single gene mutation causes a variety of typical pathological changes. So is there any way to intervene?

Gene therapy may be the most thorough method. So as I said just now, if we can repair or remove the mutated gene, we can achieve a permanent treatment effect.

Currently, any small molecule or other method is not a fundamental treatment method. Therefore, I think gene therapy should be the best way to treat this disease.

But there are difficulties here. What are the difficulties? Because this disease occurs in the brain, how to deliver these gene therapy vector tools to the brain? How to treat specific mutated genes in the entire brain? In addition, it is generally difficult to start gene therapy at a very early stage, and there are many ethical issues in intervening during conception or other stages. Then the only way must be to try to achieve treatment when the patient is about to show symptoms.

It is still quite challenging to completely cure this disease, but it is possible to improve the patient's symptoms or slow the progression of the disease through methods such as gene therapy.

Why do I say that? I just said that this disease mainly affects the nerve cells in the striatum, an important part of the brain, and the striatum controls motor coordination. Therefore, most patients have poor motor function and may even die. For example, many Huntington's patients die from respiratory diseases, especially pneumonia, because they have difficulty controlling their breathing, which can lead to pneumonia and even death.

Therefore, if this part of the function can be improved, it can actually delay the progression of the disease and allow patients to live longer. From a treatment perspective, this is quite meaningful. We believe that repairing genes in the brain and improving patients' symptoms should be a more feasible treatment method.

At present, it is difficult to treat genetic diseases with drugs (small molecules and large molecules). Now everyone is developing new gene therapy methods, and I think Huntington's disease can also be used as a very good case to try this method.

This article is a work supported by the Science Popularization China Creation Cultivation Program

Team/Author: Deep Science

Reviewer: Liang Qianjin, Professor of School of Life Sciences, Beijing Normal University

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.