Human Molecular Genetics Advance Access published online on February 19, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh093
© 2004 by Oxford University Press
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1 Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 10, Room 6C103 MSC1589, Bethesda, MD 20892, USA
* To whom correspondence should be addressed. E-mail: hardyj{at}mail.nih.gov.
Loci underlying autosomal dominant forms of most neurodegenerative disease have been identified: prion mutations cause Gerstmann Straussler syndrome and hereditary Creuzfeldt-Jakob disease, tau mutations cause autosomal dominant frontal temporal dementia, and
Article
The law of mass action applied to neurodegenerative disease: a hypothesis concerning the aetiology and pathogenesis of complex diseases
Abstract 
-synuclein mutations cause autosomal dominant Parkinson's disease. In all these cases, the mutation is in the protein that is deposited in the diseased tissue and in these cases the whole protein is deposited. In Alzheimer's disease, mutations in APP or presenilin 1 or 2 cause autosomal dominant disease and these are the substrate and proteases respectively which are responsible for the production of the deposited peptide, A
. Thus in all cases, the mutations lead to the disease by a mechanism that involves the deposition process. We briefly review this remarkably predictable biology, but also point out that it seems sporadic forms of all these diseases are predisposed to by genetic variability at the same loci, strongly suggesting that the quantity of the normal protein produced influences risk for the sporadic forms of the disease. The evidence for this assertion is strongest in Parkinson's disease (PD) where genetic variability in -synuclein expression affects risk of developing disease, although the oldest evidence for the notion that increased expression of normal sequence protein can lead to disease comes from the observation of Alzheimer's disease in trisomy 21 cases. From these observations, we make predictions concerning the aetiology and pathogenesis of neurodegenerative diseases in general.
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