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Scientists uncover master key in development of Huntington’s Disease.

Scientists from The Scripps Research Institute (TSRI) have uncovered a major contributor to Huntington’s disease, a devastating progressive neurological condition that produces involuntary movements, emotional disturbance and cognitive impairment.

Using an animal model of Huntington’s disease, the new study shows that signalling by a specific protein can trigger onset of the disease and lead to exacerbation of symptoms. These findings, published in the the journal Science Signaling, offer a novel target for drug development.

It has been more than 20 years since scientists discovered that mutations in the gene huntingtin cause Huntington’s disease; the product of the gene, Huntingtin protein, is widely expressed is almost all of the cells in the body.  The disease results in an early loss of neurons in the striatum, part of the forebrain that is responsible for coordinating thought with movement, when a person wants to move their arm, the striatum lets their muscles know. Unfortunately, the precise physiological role for huntingtin in disease onset and progression remains unclear.

The new study, however, shows for the first time a functional connection between huntingtin and mTOR, a developmentally important gene that integrates signals from multiple pathways, such as growth factors and hormones, to regulate a variety of critical cell functions. Specifically, the scientists found that the huntingtin protein activates signalling by a protein complex known as mTORC1 (mechanistic-target of rapamycin kinase (mTOR) complex 1). Depleting huntingtin reduces mTORC1 activity; an overexpression of huntingtin increases it.

In previous work the team showed that there is a protein in the striatum that interacts with huntingtin and makes it more toxic, this protein can activate mTORC1.  What the researchers didn’t know was how TORC1 and huntingtin were related. What they found for the first time in this new study is that huntingtin can activate mTORC1 and increase its activity in the striatum of mice, thus prematurely initiating the disease.

In the new research the team selectively deleted a gene that inhibits mTORC1 activity in the animal model striatum, which caused a relatively rapid increase in the severity of behavioural abnormalities related to Huntington’s disease, as well as premature death.

This indicates for the first time that huntingtin is a novel regulator of mTORC1 activity that contributes to the pathogenesis of the disease, at least in animal models.  The team summise that huntingtin may regulate mTORC1 both in the brain and in other tissue.  The suspicion is that this exacerbation of mTORC1 might compromise autophagy, the pathway that recycles proteins and organelles, which has been implicated in neurodegeneration.

The team conclude that reducing mTORC1 activation either through drugs or low-protein foods may have a positive influence on preventing the disease process.

The researchers will continue to investigate the role of mTORC1 in Huntington’s and other age-dependent neurodegenerative diseases.

Source:  The Scripps Research Institute (TSRI)

 

AAV-GFP expression in the striatum of a TSC1 flox/+/HD mouse.  Immunofluorescence image showing adeno-associated virus (AAV)-GFP microinjection (GFP flourescence) that covered 40-60% of the striatum. Image is representative of 5 to 7 mice per group.  Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington’s disease.  Subramaniam et al 2014.
AAV-GFP expression in the striatum of a TSC1 flox/+/HD mouse. Immunofluorescence image showing adeno-associated virus (AAV)-GFP microinjection (GFP flourescence) that covered 40-60% of the striatum. Image is representative of 5 to 7 mice per group. Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington’s disease. Subramaniam et al 2014.

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