Modeling sporadic Parkinson's disease by silencing the ubiquitin E3 ligase component, SKP1A.

Large-scale transcriptomics analysis of gene expression profile of sporadic Parkinson's disease (PD) substantia nigra (SN) has identified a number of differentially expressed genes participating in the neurotoxic cascade of DA neurons death, in particular those related to handling of proteins, dopaminergic transmission and iron metabolism. One of them, SKP1A (p19, S-phase kinase-associated protein 1A), an essential component of the ubiquitin-E3 ligase Skp1, Cullin 1, F-box protein (SCF) complex, has been found to be significantly decreased in the SN pars compacta of post-mortem parkinsonian brains. Recently, a new genetic cell model of sporadic PD was developed by knocking-down SKP1A in SN-derived cell-line infected with short hairpin RNA lentiviruses. SKP1A deficiency resulted in increased susceptibility to cell death and a decline in the expression of dopaminergic phenotypic markers. SKP1A-silenced cells were unable to arrest at G(0)/G(1,) when induced to differentiate, entering into an aberrant cell cycle and progressive death. During this process the cells developed rounded aggregates with characteristics of LB-like inclusions (aggresomes) including immunoreactivity for gamma-tubulin, alpha-synuclein, ubiquitin, tyrosine hydroxylase, Hsc-70 and proteasome subunit. In conclusion, future studies should focus on a careful consideration of crucial dopaminergic interacting genes, as emerged from human sporadic PD, which will serve as a basis for the development of a slowly progressive genetic animal model of sporadic PD, with the potential of evaluating drugs with "disease modifying activity".