Silencing/Overexpressing Selected Genes as a Model of Sporadic Parkinson's Disease

Background: High-throughput gene-based platform studies in human postmortem substantia nigra (SN) from sporadic Parkinson's disease (PD) cases have revealed significant dysregulation of genes involved in biological processes linked to previously established neurodegenerative mechanisms in both sporadic and hereditary PD. Objective: Our study aimed to develop a new genetic model of PD by modulating the expression of single genes that were found to be most significantly affected in SN of sporadic PD. Methods: SN-derived cell line (SN4741 cells) was infected with short hairpin RNA lentiviruses carrying different gene-specific sequences. Results: Silencing of the E3 ligase ubiquitin SKP1A resulted in a decline in the expression of dopaminergic phenotypic markers together with progression into an aberrant cell cycle and death. Furthermore, added knockout of the dopamine-metabolizing enzyme aldehyde dehydrogenase, found almost absent in sporadic PD SN pars compacta, exacerbated the vulnerability of SKP1A-silenced neurons to MPP+ and neurotrophin deprivation. Conclusion: Future studies should focus on a careful consideration of crucial dopaminergic gene network interactions 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'. Copyright (C) 2010 S. Karger AG, Basel