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Yale J Biol Med. 2013 Jun 13;86(2):217-33. Print 2013 Jun.

Huntington's disease: the past, present, and future search for disease modifiers.

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Randolph-Macon College, Department of Biology, Ashland, Virginia 23005, USA.


Huntington's disease (HD) is an autosomal dominant genetic disorder that specifically causes neurodegeneration of striatal neurons, resulting in a triad of symptoms that includes emotional, cognitive, and motor disturbances. The HD mutation causes a polyglutamine repeat expansion within the N-terminal of the huntingtin (Htt) protein. This expansion causes aggregate formation within the cytosol and nucleus due to the presence of misfolded mutant Htt, as well as altered interactions with Htt's multiple binding partners, and changes in post-translational Htt modifications. The present review charts efforts toward a therapy that delays age of onset or slows symptom progression in patients affected by HD, as there is currently no effective treatment. Although silencing Htt expression appears promising as a disease modifying treatment, it should be attempted with caution in light of Htt's essential roles in neural maintenance and development. Other therapeutic targets include those that boost aggregate dissolution, target excitotoxicity and metabolic issues, and supplement growth factors.


HD; Htt; Huntington’s disease; RNAi; autosomal dominant; developmental disorder; excitotoxicity; gain of function; gene therapy; huntingtin; loss of function; neurodegenerative disease; polyQ; polyglutamine expansions; protein misfolding; small molecule therapies; triplet repeat disorders

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