A research group from Vancouver has recently shed new light on Huntington Disease’s pathogenesis, focusing their attention on palmitoylation of huntingtin by HIP14 as a key-process in generating toxic aggregates (Yanai A., et al. Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function. Nature Neuroscience 9, 824-831, 2006). However, many features related to development of the disease remain obscure.

Huntigton Disease (HD), first described in 1872 by George Huntigton in a Long Island family suffering from a hereditary form of chorea, is a result from a mutation in a gene called huntingtin found on chromosome 4, which contains CAG triplet coding for glutamine repeated dozens of times. HD is therefore considered a Neurodegenerative Triplet Repeat Disorder, which is characterized by 3-base-pair nucleotide repeats that lie in either coding or non-coding regions, giving rise to translated polyglutamine (polyQ) tract in huntingtin (HTT), responsible for toxic aggregate formation.

Three independent groups found that CCT (also known as TRiC) can direct HTT away from forming the toxic aggregates that characterize the devastating pathology of Huntington’s disease (1. Kitamura A., et al., Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state. Nature Cell Biol. 8, 1163-1169, 2006; 2. Behrends C., et al., Chaperonin TRiC promotes the assembly of poliQ expansion proteins into non-toxic oligomers. Mol. Cell 23, 887-897, 2006; 3. Tam S., et al., The Chaperonin TriC controls polyglutamine aggregation and toxicity through subunit-specific interactions. Nature Cell Biol. 8, 1155-1162, 2006).

The correct folding of newly synthesized proteins is regulated by a pathway that involves heat-shock proteins and chaperonins, such as CCT, a cytoplasmic protein that is made up of two rings of eight homologous subunits, stacked back-to-back, that form a cage in which the normal folding reactions of many proteins have been shown to occur. The three research teams demonstrated  that overexpression of CCT can prevent the formation of mutant HTT aggregates when it is expressed in yeast cells, mammalian cell lines and neurons. In all cases this was associated with reduced apoptosis. Mutant HTT, in presence of CCT, forms non-toxic aggregates.

Summarizing findings from all the three papers, it seems that mutant HTT can oligomerize by mechanisms that can lead to formation of either toxic or benign aggregates, and part of CCT subunit 1 promotes a non-toxic HTT aggregation pathway. These findings let us hope that new molecules modelled on the CCT binding site might serve as therapies against this devastating neurodegenerative disorder.


For an accurate and updated review on HD, see Siegel, Albers, Brady, Price [Editors] BASIC NEUROCHEMISTRY, VII Edition, Academic Press 2006, pages 661-662 (genetics) and the chapter 46  [Neurotransmitters and Disorders of the Basal Ganglia]. A summary is found in C. U. M. Smith, ELEMENTS OF MOLECULAR NEUROBIOLOGY, III Edition, Wiley & Sons, Ltd. 2002, pages 516-518.


BM&L-November 2006