Alzheimer's, Huntington's and Prion Diseases - why are misfolded proteins so interesting, but so destructive?





V.M. Ingram, B.J. Blanchard, A. Ahmad, L. Zhang, L. Rozeboom

Dept. of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA



A misfolded protein can lead to neurodegeneration when the new peptide or protein conformation acquires a new physiological activity that is deleterious to cells or to organelles. The amino acid sequence may be perfectly normal, but the new conformation has new properties. We become aware of these events, if the misfolded protein is harmful and causes a disease, a gain of (unwanted) function. Alzheimer's Disease. A current hypothesis holds that in this disease the Alzheimer peptides, Aß1-40 and especially Aß1-42, are overproduced from the precursor protein for one of several reasons. They keep their normal amino acid sequence. Once free of the constraints of the parent protein they refold to form a hairpin. The hairpins then form medium-sized oligomers, apparently via ß-sheet bonds. This process is followed by fibril formation, also using ß-sheet conformations. Apparently, the misfolding is not corrected by chaperones. Both oligomers and fibrils are toxic to neuronal cells by separate mechanisms leading to dysfunction and cell death. We have developed two series of small molecules that potentially eliminate the toxicity of the oligomers and of the fibrils. Some block the cytotoxic events, others can prevent or destroy fibril formation. They are candidate compounds for the therapy of Alzheimer's, as well as other ß-sheet-based diseases, such as Huntington's and the Prion Diseases. Huntington's Disease The signature protein of the disease, huntingtin or htt, is very different. The mutant form leads to an autosomal dominant condition. In exon1 of htt there is a stretch of polyglutamine residues, normally <35 residues. In the disease this lengthens through an unknown process to 40-80 glutamines. Now htt-exon1Q>40 will aggregate in the cytosol and even in the nucleus, particularly of the spiny neurons of the striatum, making them dysfunctional. Control of movement is compromised. We can measure the rate of aggregate formation in transfected cells expressing the mutant htt-exon1. This aggregation can be modulated through addition of a small molecule that we have developed. Prion Diseases Mammalian infectious prion proteins are the misfolded conformation of a normal protein. This conformation has the unusual property of causing the normally folded protein to become equally misfolded. Apparently this conformation is infectious and causes CNS damage. Some of our small molecules promise to make the misfolded conformation harmless.




Key words: Alzheimer's, Huntington's, Prion, misfolded peptides







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