Huntington's disease mutation alters the protein needed for cell motility

Since 1993, the year of the identification of the gene responsible for Huntington's disease (HD), we have been very keen to understand how this genetic mutation led to a serious progressive neuronal deterioration of the disease. In a new study published in the Journal of Huntington's Disease, researchers have discovered that the HD mutation could alter the interactions of huntingtin, the fat protein produced by the HD gene, with Rac1, a protein that directs modifications. of the shape of the cells. In HD, this interaction can lead to abnormalities in the pathway controlling the shape of neuronal cells and dendritic growth, which can affect the quality of communication between nerve cells.

"We are delighted with this discovery because it describes a functional change occurring early in HD models, including in human neurons, that may underlie the earliest changes experienced by HD patients. Currently, Rac1 is a major investigational target in the field of cancer and Crohn's disease. Research is therefore underway on compounds likely to modify its function. Thus, we can leverage the knowledge gained by other clinicians and researchers to help us identify potential early interventions for HD, "said Kimberly Kegel-Gleason, PhD, Cellular Neurobiology Laboratory, Department of Neurology, Mbadachusetts. General Hospital, Charlestown, MA, USA. .

The ability of a cell to change shape is important for the ability of cells to move (migrate) and allow neurons to connect and communicate with each other. Rac1 directs changes in cell shape by altering actin dynamics in response to extracellular signals (growth factors) downstream from an important cellular enzyme called PI 3-kinase. Actin is a protein that contributes to the contractile capacity of muscle and other cells. The purpose of this study was to determine whether the activity of RAC1 is impaired in HD or regulated by normal huntingtin, which could explain some of the pathological changes seen in HD neurons.

The researchers discovered early changes in the level of Rac1 activity in HD human neural cells and the mouse HD striatum. They showed that huntingtin (normal and mutant) and PI-3 kinase preferentially badociate with the active form of Rac1. Normal neuronal cultures and HD reacted very differently to the reduction of total huntingtin protein. The cells responded to a reduction in total huntingtin by increasing Rac1 activation. However, lowering total huntingtin levels (normal and mutant) in HDM neuron cultures appeared to counteract an abnormal increase in Rac1 activation. "These data suggest that ongoing trials using cholesterol-lowering reagents may be beneficial to HD patients, but that the same treatment could be quite toxic to normal individuals," commented Dr. Kegel-Gleason.

This research has also identified a functional change that affects a pathway controlling the shape of cells, including the shape of connections called dendrites. Dendrites are like fingers irradiated by neurons that receive information from other neurons. The shape of these "fingers" can influence the strength of the connections between neurons and, hence, the total connectivity of the neural network. The researchers suggest that the excess activation of RAC1 could be the molecular mechanism underlying changes in the form of dendrites emanating from HD neurons. This can be very important to understand the early changes observed in HD before motor symptoms. Abnormalities in dendrite growth and spine density of average spiny neurons have been detected in the brains of HD patients. These structural changes may alter the ability of neurons to function and interact properly in the case of Huntington's disease.

"We believe that the activity of Rac1 is a control point of the PI 3-kinase / Rac / actin pathway and that its modulation is possible with the help of small chemicals. There is still a lot of work to do to determine in which direction we should be modulating this path and how this will affect downstream targets, but it is a good starting point, "said Dr. Kegel-Gleason. "While huntingtin reduction reagents look promising, some symptoms could be corrected by less aggressive measures earlier in the disease."

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Reference:

Tousley, A., et al. (2019). Rac1 activity is modulated by huntingtin and deregulated in Huntington's disease models. Journal of Huntington & # 39; s Disease 8: 53-69