Scientists have uncovered signaling by a specific protein can trigger onset of the disease and lead to exacerbation of symptoms and a major contributor to Huntington's disease.
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 you want to move your arm, the striatum lets your muscles know. Unfortunately, the precise physiological role for huntington in disease onset and progression remains unclear.
The new study, however, shows for the first time a functional connection between Huntington 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 Huntington protein activates signaling by a protein complex known as mTORC1 (mechanistic-target of rapamycin kinase (mTOR) complex 1). Depleting Huntington reduces mTORC1 activity; an overexpression of Huntington increases it.
Srinivasa Subramaniam, a TSRI biologist who led the study, said that in their previous work, they showed that there is a protein in the striatum that interacts with huntingtin and makes it more toxic—this protein can activate mTORC1.
He said that what they 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, Subramaniam and his colleagues selectively deleted a gene that inhibits mTORC1 activity in the animal model striatum, which caused a relatively rapid increase in the severity of behavioral abnormalities related to Huntington's disease, as well as premature death.
Researchers said that they think that Huntington may regulate mTORC1 both in the brain and in other tissue and their suspicion is that this exacerbation of mTORC1 might compromise autophagy—the pathway that recycles proteins and organelles—which has been implicated in neurodegeneration.
Scientists added that reducing mTORC1 activation either through drugs or low-protein foods may have a positive influence on preventing the disease process.
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