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
alpha-synuclein mutations cause autosomal dominant
Parkinson's disease. In all these cases, the pathogenic 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, Abeta. 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
alpha-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 etiology and pathogenesis of
neurodegenerative diseases in general.