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.


CONCLUSIONS
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'.
Fishman-Jacob
Tali
T
Eve Topf Center for Neurodegenerative Diseases Research and Department of Molecular Pharmacology, Faculty of Medicine, Technion, Haifa, Israel.
Youdim
Moussa B H
MB
Mandel
Silvia A
SA
D000818:Animals; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D008954:Models, Biological; D010300:Parkinson Disease / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D034622:RNA Interference / Q000502:physiology*; D037941:Silencer Elements, Transcriptional / Q000235:genetics / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
D044767:Ubiquitin-Protein Ligases