Genetic variability in the alpha-synuclein gene and long-term exposure to the pesticide paraquat constitute possible risk factors for sporadic Parkinson's disease.
Further, the "protective" genotype 259/259 of the PD-associated promoter repeat NACP-Rep1 is associated with lower protein levels in blood than genotypes 261/261, 259/261, and 259/263.
We hypothesize dysregulated expression of wild-type alpha-synuclein results in parkinsonism and may explain the recent association of common SNCA variants in sporadic Parkinson's disease.
Genetic mouse models based on alpha-synuclein overexpression are particularly compelling because abnormal accumulation of alpha-synuclein occurs in sporadic Parkinson's disease (PD).
We found that the levels of these interactions were aberrantly increased by the I93M mutation, and that expression of I93M UCH-L1 in cells induced the CMA inhibition-associated increase in the amount of alpha-synuclein, a risk factor for PD.
These data indicate that overexpression of alpha-synuclein is sufficient to cause olfactory deficits in mice similar to that observed in patients with PD.
Although the etiology for sporadic Parkinson's disease is unknown, information gleaned from both familial forms of the disease and animal models places misfolded alpha-synuclein at the forefront.
These findings reveal a significant additional mechanism by which alpha-synuclein is regulated and point toward new therapeutic regimes for lowering endogenous alpha-synuclein levels in patients with familial or sporadic Parkinson disease.
The protein alpha-synuclein accumulates in the brain of patients with sporadic Parkinson's disease (PD), and increased gene dosage causes a severe, dominantly inherited form of PD, but we know little about the effects of synuclein that precede degeneration. alpha-Synuclein localizes to the nerve terminal, but the knockout has little if any effect on synaptic transmission.
These results demonstrate biochemical abnormalities of alpha-synuclein, and increased oxidative stress damage and oxidative stress responses in the frontal cortex in PD linked with G2019S LRRK2 mutation not related with the presence of cortical LBs and in the absence of apparent cognitive deficits.
Increased availability of the fibrillogenic protein substrates of the pathological aggregates that define several neurodegenerative proteopathies, eg α-synuclein in PD, β-amyloid in AD and tau in the tauopathies, contributes to causation and risk in the familial and sporadic forms of these disorders, respectively.
We provide evidence for functional consequences of PD-associated SNCA gene variants at the 3' region, suggesting that genetic regulation of SNCA splicing plays an important role in the development of the disease.
However, the mechanisms by which subtle variations in the expression of wild-type SNCA and MAPT influence risk for PD and the underlying cellular events that effect neurotoxicity remain unclear.
Brain regions with and without a Parkinson's disease-related increase in α-synuclein levels were assessed in autopsy samples from subjects with sporadic Parkinson's disease (n = 19) and age- and post-mortem delay-matched controls (n = 10).
Post mortem studies on familial and sporadic Parkinson's disease patient striatal tissue have shown that nearly 90% of α-synuclein deposited in Lewy-bodies is phosphorylated at serine-129 (pSyn-129) as opposed to only 4% in normal human brain.