Genetic reduction of the E3 ubiquitin ligase element, SKP1A and environmental manipulation to emulate cardinal features of Parkinson's disease.

AIMS:To assess whether reduction of Skp1 will increase the vulnerability of dopaminergic neurons to genetic/environmental factors known to play a role in the pathological process of PD. METHODS:Short hairpin RNA lentiviruses infection of substantia nigra (SN)-derived cell-line (SN4741) and mice intranigral injection. RESULTS:We have knocked down the expression of SKP1A, an E3 ubiquitin ligase element, found significantly decreased in human SN in patients with PD. The deficiency of SKP1A in SN4741 cells closely recapitulated cardinal features of the dopamine (DA) neuron pathology of human PD, such as decreased expression of DA phenotypic markers and cell cycle aberrations. Moreover, the knocked down cells displayed a lethal phenotype in differentiated cells exhibiting proteinaceous round inclusions, which were almost identical in composition to human Lewy bodies. Knock down of SKP1A rendered SN4741 cells especially sensitive to genetic reduction of the DA metabolizing enzyme, aldehyde dehydrogenase 1 and exposure to external Stressors implicated in PD pathology. CONCLUSION:Future studies should contemplate intrinsic and environmental manipulations in Skp1-deficient animals to emulate the motor and non-motor disabilities, the progressive nature of PD, and striatal-nigral and adjacent areas pathology. This model may provide a reliable "platform" to develop new therapeutic interventions for PD.

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