30 Oct Study Identifies Potential Target In Huntington’s Disease Pathway
Medical Research: What is the background for this study? What are the main findings?
Dr. Subramaniam: Huntington’s disease (HD) is a genetic disorder occurs due to a mutation in a protein called huntingtin (mHtt), which affects 5-10 people per 100000 populations worldwide. Our research revolves around the question— why mutant huntingtin despite its ubiquitous expression through out the body selectively affects brain regions such as striatum, a region that regulates voluntary movement. We now found that mHtt activates a protein kinase complex, mammalian target of rapamycin complex 1 (mTORC1), which is required for normal functions such as translation of genes into proteins and also organelle recycling. We found the mTORC1 activation is so robust and sustained in the striatum that lead to the severe motor disabilities and premature death of HD mice. Our study indicates a functional relationship between huntingtin and mTOR the developmentally important genes with implication in Huntington’s disease pathogenesis.
Medical Research: What should clinicians and patients take away from your report?
Dr. Subramaniam: Striatum is a hub for signaling molecules, which control striatal functions and motor activity. It is important to understand how these molecules are altered to known exactly what happens in Huntington’s disease striatum. Our reports suggests In Huntington’s disease, these signaling in striatum are exaggerated by mHtt in association with specific signaling modulators. Although the nature of such modulators is less clear, we have some evidences that suggest Rhes GTPase can be one such modulator. An interesting thing is mTORC1 activity is vital to all cells, and may be necessary for the normal motor functions in striatum, but when that activity is too much that lead to a disease state. Paradoxically, mTORC1 inhibitors in the normal mice can prolong the lifespan indicating less mTORC1 might have overall balanced benefit to the organism. Our report says mHtt interferes with fundamental balance by forming a tight complex with mTORC1 and accelerates aging, and aging-related motor deficit as seen, in Huntington’s disease.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Subramaniam: From therapeutic perspective, we need focus on striatal specific regulators and how they modulate mHtt-mediates mTORC1 pathway. Interestingly, nutrients such as glucose and amino acids (plenty in our food) can have a profound effect on mHtt-mediated mTORC1 activation, suggesting an abnormal nutrient signaling may influence Huntington’s disease progression. Thus our study implies that drugs or low calorie/protein diets, which lowers mTORC1 activities, may have therapeutic benefits in Huntington’s disease, although that needs to be confirmed first through experiments in mice. More studies dissecting the upstream and downstream of Htt–mTORC1 pathway would help generate chemical drugs that can be selectively targeted to one or more component of these pathways that might effectively delay or prevent Huntington’s disease pathogenesis.
W. M. Pryor, M. Biagioli, N. Shahani, S. Swarnkar, W.-C. Huang, D. T. Page, M. E. MacDonald, S. Subramaniam. Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington’s disease. Science Signaling, 2014; 7 (349): ra103 DOI: 10.1126/scisignal.2005633