Extensive evidence has accumulated in recent years that several human disorders have the same molecular basis, namely, a change in the conformation of a protein. These disorders have been named "conformational diseases" , and the most important among them are prion and Alzheimer diseases. Prion diseases have been proposed to be caused by the transconformation of the cellular prion protein PrPc into a protease-resistant and readily aggregated isoform (PrPSc) which accumulates in the brain. However, controversy exists regarding exactly where and how in the cell this conversion occurs. Conversely, in Alzheimer's disease (AD) mutations in genes encoding three different proteins, amyloid precursor protein (APP) and presenilins 1 and 2 have been shown to lead to the overproduction and accumulation in the brain of the amyloid peptide Ab that converts from a soluble form into amyloid fibrils. During its biogenesis, APP undergoes sequential enzymatic cleavages, and a critical question for understanding the pathogenesis of Alzheimer's disease is where, and at what rate, Ab is produced in neurons. In the case of prion diseases, it has been postulated that missorting of APP or altered intracellular trafficking of Ab could play a key role in the pathogenesis of AD (2,3).
Lipid rafts, which are small membrane patches of highly ordered saturated lipids and cholesterol, have been proposed to play a role in the biogenesis of both these neurodegenerative disorders because they might represent a preferential site for the formation of the pathological forms of the prion protein and amyloidogenic Ab. Thus, for both conformational diseases it appears that the intracellular trafficking of PrPc and APP, and their association with rafts, have a predominant role in their related pathogenesis. Here, we review the latest findings on these two fundamental aspects.
206 | 10 Lipid Rafts in Trafficking and Processing of Prion Protein and Amyloid Precursor Protein 10.2
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