Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: ‘permissive templating’ as a general mechanism underlying neurodegeneration

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Abstract
Loci underlying autosomal dominant forms of most neurodegenerative disease have been identified: prion mutations cause Gerstmann Straussler syndrome and hereditary Creutzfeldt–Jakob disease, tau mutations cause autosomal dominant frontal temporal dementia and α-synuclein mutations cause autosomal dominant Parkinson's disease. In these cases, the pathogenic mutation is in the protein that is deposited in the diseased tissue and the whole protein is deposited. In Alzheimer's disease, mutations in amyloid precursor protein or in the presenilins cause autosomal dominant disease. These are the substrate and proteases responsible for the production of the deposited peptide Aβ. Thus, in all the cases, the mutations lead to the disease by a mechanism that involves the deposition process. Furthermore, sporadic forms of all these diseases are predisposed by genetic variability at the same loci, implying that the quantity of the normal protein influences the risk of this form of disease. These results show that the amount of pathogenic protein expression is a key factor in determining disease initiation. Recent work on transgenic models of these diseases is consistent with the view that there are two stages of pathogenesis: a concentration-dependent formation of a pathogenic protein oligomer followed by aggregation on to this oligomeric template by a process that is less dependent on the concentration of the protein.