Basically, my interest since many years is to first understand the function of huntingtin, the protein that is mutated in Huntington’s Disease and to try to better understand how alteration of this function could participate to the disease.
And so, the overall idea is to try to delineate the pathways that are altered or that are regulated by the protein, how those pathways or those functions are dysregulated when the huntingtin protein contains the mutation, and how this can actually participate to the pathogenic process...
Basically, my interest since many years is to first understand the function of huntingtin, the protein that is mutated in Huntington’s Disease and to try to better understand how alteration of this function could participate to the disease.
And so, the overall idea is to try to delineate the pathways that are altered or that are regulated by the protein, how those pathways or those functions are dysregulated when the huntingtin protein contains the mutation, and how this can actually participate to the pathogenic process. With, of course, I mean, the idea that if we understand those processes that are affected by the protein, this might be early events in the disease. And so, we might find ways to intervene and maybe have therapeutic interest or strategy of therapeutic interest. That’s basically the idea of the overall.
And so, now what we discovered almost 20 years ago now is that the huntingtin protein plays a direct role as facilitating the transport of trophic factors in the brain and especially within the corticostriatal circuit in the brain. This is going to be very important because this circuit is absolutely crucial for the maintenance of both the cortical neurons and the striatal neurons, the two type of neurons that degenerate in the disease.
The overall idea and the work I’ve done, work done in the lab since many years, is that we really have evidence now that this axonal transport is key and is a very early event that will actually lead to the sensitization of the striatal neurons and the cortical neurons to neural degeneration. Of course now the focus is trying to ameliorate the transport or rescue the transport that is altered in disease. We know that there is… I mean, axonal transport is highly regulated process, and so it’s bidirectional. It goes from the cell body to the axon terminals. Where for example, this trafficking will bring, not only traffic factors that are important for the maintenance of the synapse, but also neurotransmitters that will be released at the synapse and that participate to neuronal communication.
Of course, I mean, our previous work actually has shown that huntingtin transports vesicles that contain BDNF. Therefore, it directly controls, I would say, the synapse maintenance. More recent work from the lab is that, not only the trophic factors released at the synapse control the survival of the striatal neurons, but it has also a feedback mechanism by which it also control the survival of the cortical striatal projecting neurons. The afferents that it comes from the cortex to the striatum. We have a whole maintenance of just the survival or the functioning of the neurons.
Then on top of that, and this is some work that has been where we started to work on it. And then, we start to have more and more evidence and that’s something we are following up, that we believe that in addition huntingtin controls also the trafficking of other organelle, not just the vesicles that contain these trophic factors, but also basically that contain the neurotransmitter. Therefore, it could play a role in the neuronal communication. In that, and also because BDNF, by controlling the synapse or neurostasis, is also going to have an impact on neuronal communication. The consequence of this is that you have defect in the communication between cortex and striatum with alteration in the activation of the striatal neurons, which probably are responsible for this alteration of neuronal response in the patient, like this abnormal, impulsive behavior or this choreic movement or this, yeah.
