Huntington's research heats up: A review of the role of heat shock proteins in HD

HD Lighthouse Contributing Editor's Comment: The paper by Wacker and colleagues (below) does not propose an immediate treatment of HD, but it does shed light on a process that we believe goes to the heart of HD pathology. This process is called oligomerization, which means the clumping together of proteins. In the case of HD, it has been known for some time that the HD protein, huntingtin, tends to oligomerize and to form larger clumps called aggregates or inclusions. Our own experience in modeling huntingtin on computers has led us to believe that the extra stickiness of abnormal huntingtin, which leads to the clumping, has got to be central to HD. If this turns out to indeed be the case, then the insights in this paper may result in therapies that are 1) more effective than those available today or in the near future, e.g., creatine, and 2) closer to being ready than more exotic therapies, e.g., RNA interference.

Huntington's disease, and other neurodegenerative disorders, are known for abnormal protein clumping. In the case of HD, these clumps have been known as aggregates or inclusions. When they were first discovered, aggregates were hailed as the "smoking gun" of HD. They were seen as the perfect therapeutic target: If we could stop aggregation, perhaps we'd have a cure. However, it was soon discovered that aggregates were not always in the sickest cells, and that some of the sickest cells did not even have aggregates. In a few years, it was even suggested that aggregation was a way in which the cell protected itself.

What Wacker and colleagues found is that there is another, more microscopic form of clumping. Furthermore, this form, called oligomerization, comes in very characteristic shapes - spherical and doughnut shaped. While this may not sound like such a stunning discovery, it is actually very important, since the same shaped clumps are found in other neurodegenerative diseases, e.g., Alzheimer's disease, Parkinson's disease, etc. And it has been shown in these other diseases that clumps with these shapes are, unlike the aggregates, toxic.

Even this much would be an important discovery, since identifying the toxic clumps could aid other researchers in their quest for therapeutics. But the paper goes further. It identifies certain proteins from a class known as heat shock proteins that slow down the creation of these toxic clumps. This is especially exciting to us, since heat shock proteins are from a larger class (molecular chaperones) that help keep proteins in their proper shape (i.e., they keep proteins properly folded). It is well known that the HD protein, huntingtin, has a different shape than the normal version and that this shape makes it stickier, i.e., more likely to clump. Therapeutics similar to the heat shock proteins identified in the paper may, therefore, prevent the clumping and in so doing, prevent or slow down the disease. The fact that a similar clumping occurs in Alzheimer's and Parkinson's is just icing on the cake, since it means that all those researchers who work on those other diseases would also be working for us.

So, the paper does two things: 1) It helps bridge a gap in our knowledge - between the shape of huntingtin (Figure 1) and the disease pathology and 2) it suggests a potential source of therapeutics that may go to the heart of the beast.

--Malcolm Casales, Ph.D.

- image courtesy of MacDonald ME. Huntingtin: alive and well and working in middle management. Sci STKE. 2003 Nov 4;2003(207):pe48. Print 2003 Nov 4.

Authors:Wacker JL, Zareie MH, Fong H, Sarikaya M, Muchowski PJ

Protein conformational changes that result in misfolding, aggregation and amyloid fibril formation are a common feature of many neurodegenerative disorders. Studies with beta-amyloid (Abeta), alpha-synuclein and other amyloid-forming proteins indicate that the assembly of misfolded protein conformers into fibrils is a complex process that may involve the population of metastable spherical and/or annular oligomeric assemblies. Here, we show by atomic force microscopy that a mutant huntingtin fragment with an expanded polyglutamine repeat forms spherical and annular oligomeric structures reminiscent of those formed by Abeta and alpha-synuclein. Notably, the molecular chaperones Hsp70 and Hsp40, which are protective in animal models of neurodegeneration, modulate polyglutamine aggregation reactions by partitioning monomeric conformations and disfavoring the accretion of spherical and annular oligomers.

Tracked on the Lighthouse:
aggregates
heat shock proteins

Source: Nat Struct Mol Biol. 2004 Nov 14

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