There may be common pathogenetic mechanisms involved in alpha-synuclein mutations in PD and beta-amyloid and presenilin gene mutations in Alzheimer's disease.
Exploration of the possibility that the same mutation of the alpha-synuclein gene as that in familial PD (Ala53Thr) may also confer susceptibility to sporadic PD, DLB, and AD revealed the mutation in none of the samples of 329 cases and 230 controls examined, suggesting that this mutation is not involved in these neurological diseases.
A peptide of the alpha-synuclein protein had been characterized previously as a major component of amyloid plaques in brains of patients with Alzheimer's disease (AD).
Missense mutations in the alpha-synuclein gene cause familial Parkinson's disease (PD), and alpha-synuclein is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer's disease (AD).
Identification of alpha-synuclein as the first of the loci involved in Parkinson's disease and the identification of this protein in pathological deposits in other disorders has led to the suggestion that it may share pathogenic mechanisms with multiple system atrophy, Alzheimer's disease and prion disease and that these mechanisms are related to a synuclein pathway to cell death.
Alpha synuclein also contributes to the intracellular inclusions of multiple system atrophy, and a fragment has been found in senile plaques in Alzheimer's disease.
KM670/671NL have limited neuron loss and tau pathology, but frequent ubiquitin- and alpha-synuclein-positive, tau-negative neurites resembling those seen in the LBV of AD.
One of the mutant forms of alpha-synuclein (A53T) fibrillizes more rapidly in vitro than does the wild-type protein, suggesting that a correlation may exist between the rate of in vitro fibrillization and/or oligomerization and the progression of PD, analogous to the relationship between Abeta fibrillization in vitro and familial AD.
Analogous to a successful strategy for the production of transgenic animal models for Alzheimer's disease we generated mice expressing wildtype and the A53T mutant of human alphaSN in the nervous system under control of mouse Thy1 regulatory sequences.
The involvement of alpha-synuclein in neurodegenerative diseases was first suspected after the isolation of an alpha-synuclein fragment (NAC) from amyloid plaques in Alzheimer's disease (AD).
Analysis of the superior temporal cortex, a region selectively affected in LBD and AD, showed that compared to controls, levels of alpha-synuclein were increased in cases of diffuse LBD (DLBD), levels of beta-synuclein were decreased in AD and DLBD, and levels of gamma-synuclein were increased in AD cases.
Further investigation of alpha-synuclein and its relationship to pathological conditions promoting Lewy body formation in AD, PD, and DLB may yield further insight into pathogenesis of these diseases.
Mutations in genes that cause inherited forms of Alzheimer's disease (amyloid precursor protein and presenilins), Parkinson's disease (alpha-synuclein and Parkin), and trinucleotide repeat disorders (huntingtin, androgen receptor, ataxin, and others) overwhelm endogenous neuroprotective mechanisms; other genes, such as those encoding apolipoprotein E(4), have more subtle effects on brain aging.