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.
In summary, our footprint-free LRRK2-G2019S isogenic cell lines allow standardized, genetic background independent, in vitro PD modeling and provide new insights into the role of LRRK2-G2019S and S129P-αS in the pathogenesis of PD.
Alpha-synuclein was implicated in Parkinson's disease when missense mutations in the alpha-synuclein gene were found in autosomal dominant Parkinson's disease and alpha-synuclein was shown to be a major constituent of protein aggregates in sporadic Parkinson's disease and other synucleinopathies.
Gain-of-function mutations in leucine-rich repeat kinase 2 (LRRK2) cause familial as well as sporadic Parkinson's disease characterized by age-dependent degeneration of dopaminergic neurons.
No mutations were found in any of the patients, suggesting that a mutation at the coding region of the alpha-synuclein gene is unlikely to be responsible for nigrostriatal degeneration in typical 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 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.
The R1628P and G2385R polymorphisms of the LRRK2 gene have been identified as exclusively associated with PD in Asian populations, particularly in Han Chinese population.
The polymorphic mixed sequence repeat (NACP-Rep1) in the promoter region of SNCA has been previously examined as a potential susceptibility factor for PD with conflicting results.
The discovery of alpha-synuclein mutations in families with autosomal dominant Parkinson's disease sheds light on its role in sporadic Parkinson's disease.