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Editor's Comment: As we have often said on the Lighthouse, Huntington's Disease has been slow to give up its secrets. A decade ago, it seemed as if the major pathology had been identified and the way to treatment made clear. When the first mouse model of the disease was developed, clumps of the HD protein were found to be clogging up the nuclei of neurons in the mice. Researchers quickly looked to see if this was also true in the human brain and it was! There was a great deal of excitement.
I remember my first HDSA national convention which was in 1998 in Denver, Colorado. One researcher even sang a song about a cure in five years. Of course she was careful to say that no one could predict when treatments would be available, but optimism and excitement were in the air and I was told by longtime activists that there was a real turning point. As one researcher said in her presentation, "We still don't know what we don't know, but now we have the tools to get there."
Even at that convention, however,
Polyglutamine (polyQ) expansion mutation causes conformational, neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. These diseases are characterized by the aggregation of misfolded proteins, such as amyloid fibrils, which are toxic to cells. Amyloid fibrils are formed by a nucleated growth polymerization reaction.
Unexpectedly, the critical nucleus of polyQ aggregation was found to be a monomer, suggesting that the rate-limiting nucleation process of polyQ aggregation involves the folding of mutated protein monomers. The monoclonal antibody 1C2 selectively recognizes expanded pathogenic and aggregate-prone glutamine repeats in polyQ diseases, including Huntington's disease (HD), as well as binding to polyleucine. We have therefore assayed the in vitro and in vivo aggregation kinetics of these monomeric proteins. We found that the repeat-length-dependent differences in aggregation lag times of variable lengths of polyQ and polyleucine tracts were consistently related to the integration of the length-dependent intensity of anti-1C2 signal on soluble monomers of these proteins. Surprisingly, the correlation between the aggregation lag times of polyQ tracts and the intensity of anti-1C2 signal on soluble monomers of huntingtin precisely reflected the repeat-length dependent age-of-onset of HD patients.
These data suggest that the alterations in protein surface structure due to polyQ expansion mutation in soluble monomers of the mutated proteins act as an amyloid-precursor epitope. This, in turn, leads to nucleation, a key process in protein aggregation, thereby determining HD onset. These findings provide new insight into the gain-of-function mechanisms of polyQ diseases, in which polyQ expansion leads to nucleation rather than having toxic effects on the cells.
Source: PLoS ONE. 2007; 2(7): e635.
Printed: 09 Sep 2010
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Article posted to www.HDlighthouse.org on: 07-31-2007
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