HUNTINGTON DISEASE : PROTEIN PART

Introduction

Interactions between the Huntingtin and Other proteins

As we know, the Huntington disease is only due to a mutation on one gene. And this gene (called HTT) codes for the huntingtin protein which is a very important protein in the human body. Indeed, it is involved in the protection of the cell against apoptosis (which corresponds to the programmed death of the cell). But this very complex protein has also many interactions with other proteins so it is involved in many functions in the human body (we can see on the image below all the interactions which exist between the Huntingtin and other proteins). That is why we have still some difficulties to explain the Huntington disease:  there are a lot of different hypotheses. Moreover those hypotheses are not always proved but we will try to explain the most recurrent one.

Huntingtin

The HTT gene is composed of 180 kb and contains 67 exons from 48 bp to 341 bp with an average of 138 bp and the huntingtin is composed of 3,144 amino acids (on the image we can see only the N-terminus part of the protein. This is quite complex and we let you imagine what an image of the whole protein could have given...). So this protein is quite complex and it is able to create many interactions with other proteins.

Structure of the N-Terminus part of the Huntingtin

When someone has the Huntington disease, we have seen that the gene is mutated and that there is an accumulation of the CAG codon. This accumulation corresponds to the expansion of the polyglutamine part in the protein (since the protein is coded by the gene, when there is an accumulation of CAG in the gene, we find an accumulation of glutamine amino-acids corresponding to a polyglutamine part). And this polyglutamine is situated in the N-terminus part of the Huntingtin.

An analyse of several polyglutamine regions has shown dramatic conformational flexibility with an accessible hinge separating two large alpha-helical domains. This shows that the mutation of the gene is not a silent mutation and that there is a consequence on the protein structure. So if the structure of huntingtin is different, its function will change too because there are also abnormal interactions with its protein partners. That explains the Huntington disease because normally, the Huntingtin protein is a protection for the nervous cells against apoptosis. In fact the symptoms of the Huntington disease are due to the loss of nervous cells in the brain. This loss is due to the apoptosis (the death) of the nervous cells because the cells are not protected from apoptosis. Indeed the mutated huntingtin does not interact the same way than normal huntingtin so it does not protect cells agains apoptosis and they die.

Interactions between Huntingtin and other proteins

Abnormal Interactions

With BDNF: A scientist named Zuccato showed that Huntingtin regulates of the Brain-Derived Neurotrophic Factor (BDNF). Actually, this factor is produced by cortical neurons and is involved in the survival of the neuronal cells. But when the huntingtin is mutated, it does not regulate the BDNF anymore and with less BDNF the cells might die.

With HAP1: Another Scientist, Li, found a protein called Huntingtin Associated Protein 1 (HAP1). This protein is mainly located in the brain and when it forms a complex with huntingtin and p150(Glued), it increases the vesicular transport of BDNF. When huntingtin is mutated, longer is the polyglutamine part of the Huntingtin, more it will be linked with HAP1. However, the complex with p150(Glued) will not be possible and the BDNF will not be transported and there will be a loss of neurotrophic support and there will be neuronal toxicity.

With ITPR1: Moreover, Tang found a protein complex containing huntingtin, HAP1 and the type 1 inositol 1,4,5-triphosphate (IP3) receptor (ITPR1) in neurons. Indeed HAP1 help the association of Huntingtin with the C-terminus part of ITPR1. But when Huntingtin is mutated, it bounds more easily to ITPR1 and it increases the sensitization of the ITPR1 receptor to activation by IP3. Therefore the consequence is an increase of calcium level in the cell and in some cases if this level keeps increasing, it may be toxic to neurons.

With MMP10: Miller identified some processing proteases such as MMP10 and MMP14 which cleaves mutated huntingtin near the N-Terminus part. So they help the role of huntingtin in the cell but it has been observed that when there is less MMP10 or MMP14, less caspase is activated so less cells will die from apoptosis.

With Caspases: Caspases are proteins that are cysteine-dependent aspartate-specific proteases. There are two types of caspases: initiator caspases: caspase 8,10,9 and 2, and effector caspases: caspase 3,7 and 6. To be activated, initiator caspases requires bounds with specific proteins, whereas effector caspases are then activated by these active initiator caspases. This is the active effector caspases which induces the programmed death of the cell.

Graham discovered that some mutated huntingtin which resists to the cleavage by caspase-6, but not by caspase-3, maintained normal neuronal function and did not develop neurodegeneration. Moreover the cells were also protected against the neurotoxicity due to external stressors. So the scientist concluded that the cleavage of huntingtin by the caspase-6 is crucial in the Huntington Disease because that causes the illness and the abnormal degeneration of the neuronal cells.

(On the image we can see the main interactions that the Huntingtin has with other proteins. The interaction with Casp3 corresponds to the interaction with caspase)

Diseases with polyQ Expansion
: 

We know that the Huntington disease (HD) is one of the nine diseases due to polyglutamine (polyQ) expansion. They all are neurodegenerative diseases. Except the polyQ expansion, these nine proteins, involved in the disease, haven’t anything in common. So, we are going to explain the most common hypothesis regarding the cells’ death in neurodegenerative diseases.

Ubiquitin-Proteasome action

The ubiquitin-proteasome is a complex which destroys the mutant protein. Ubiquitin flags the mutant protein and proteasome destroyes them. The ubiquitin signals mutant Htt and proteasome damage the Htt by proteolysis, a chemical reaction which needs proteases (like caspase-3 and caspase-6) and cuts the mutant Htt into several small fragments. Normally, this fragment can be recycled and digested by the cell. But the polyQ expansion causes an incomplete degradation and lead to a protein aggregates. The harmful Htt fragment is due to abnormal splicing of the Htt mRNA. It is so small that it can get into the nucleus. These fragments are also recognised by the ubiquitin but the agregates alter the complex’s functions. So it leads to an accumulation of aggregates in the nucleus, which causes the death of the cells.

Cycle between aggregates and complex Ubiquitin-Proteasome

Moreover, there are also post-traduction modifications. They can modulate the toxicity with an alteration of the sub cellular localisation, of proteolysis, of aggregation or of an interaction with another partner.

For instance, an Stanford’s study shows that there is a sequence, composed by 17 amino acid (AA), allowing the Htt to get out of the nucleus and to move into the cytoplasma. But this sequence is not enough. If we look this sequence without the rest of the protein, we can observe that it stays in the nucleus. To get out, it needs another protein: the exportin 1. A point mutation in the sequence of the 17 AA causes the Htt aggregation in the nucleus.  It’s the sequence which allows the link between Htt and exportin-1.

            Furthermore, this sequence promotes the association between the Htt and the endoplasmic reticulum of the mitochondria, further preventing nuclear accumulation.

            But we don’t know how its sequence regulates the protein aggregates. 

Explanation of chorea symptoms

The HD causes the death of neurons in the brain. But some parts of the brain are most affected by the disease than others. The basal ganglia, composed by Caudate Nuclei and Putamen (striatum), is an example of a brain’s part very affected. Basal ganglia regulate most of the motor functions. We can observe a loss of this part of the brain because of the neurons death. That explains why the disease is characterized by chorea. The Cerebral Cortex is also affected. It controls the thought, the perception, and the memory. 

We can observe several holes in the brain of people who have HD. Sick people loose around 400g of brain.

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HD brain and normal brain

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Parts of the brain

Conclusion:

To put it in a nutshell, we saw that the Huntington Disease is due to the death of neurons. It causes some severe symptoms like chorea, dystonia, dementia, behavioural difficulties and psychiatric issues. Moreover, this complex illness is in fact due to one mutation, only on one gene and repeated several times. But these mutations have indeed many consequences because the gene codes for a protein called Huntingtin. Normally, this protein plays the role of protector of the cells against apoptosis (death of the cells). Since this protein is mutated and has a different sequence (because the gene has a different sequence due to the mutation), the Huntingtin can’t play its role anymore and the neurons die. But even if this illness is due to the abnormal behaviour of one mutated protein, this protein plays many roles in the brain and the body so it is very difficult to find a treatment However, the patient’s life can be improved by drugs.

This corresponds to what we saw in the other articles of this blog. Neurons control everything in the body. So, if they die, the consequence is indeed the symptoms of the Huntington Disease and this inevitably leads to death.