The altered huntingtin protein responsible for HD has been shown to contain many more molecules of the amino acid glutamine than regular huntingtin. This abundance of glutamine is due to repetitive copies of the CAG codon in the Huntington gene. The extended glutamine tracts of these proteins have affinity for one another, and tend to “stick together,” leading to the formation of “clumps” or aggregations of the protein in the cell’s nucleus. These protein aggregations are often referred to as neuronal inclusions (NIs).
It is not absolutely clear whether NIs are the cause or the result of HD, or whether they might even be a defense mechanism against it. Scientists are not certain whether the NIs themselves are toxic, or whether the intermediates or building blocks in the aggregation process are the toxic agents. These questions aside, there is mounting evidence supporting NIs as a primary mediator of cellular toxicity in Huntington’s disease.
There are two major lines of thought regarding the toxic mechanisms of polyglutamine protein aggregation. One is that other normal molecules with glutamine tracts get “trapped” within the NIs, and are therefore prevented from performing their normal functions. Another is that the NIs “clog” the Ubiquitin-Proteasome System (UPS), a kind of disposal system that is essential for normal cell function. For more information on the role of protein aggregation in the progression of HD, click here.
Scientists have shown that reducing the amount of protein aggregation in the cell may be beneficial for patients with HD. The drugs listed under the “Protein aggregation” navigation menu potentially reduce the amount of NIs in the cell, and are therefore being researched as possible treatments for HD.
-E. Tan, 9-21-01