Targeting SKP1, an ubiquitin E3 ligase component found decreased in sporadic Parkinson's disease.
Microarray-derived transcriptomic studies in human substantia nigra pars compacta (SNpc) samples from sporadic Parkinson's disease (SPD) cases have opened an avenue to concentrate on potential gene intersections or cross-talks along the dopaminergic (DAergic) neurodegenerative cascade in SPD. One emerging gene candidate identified by our group was SKP1A (p19, S-phase kinase-associated protein 1A), found significantly decreased in the SNpc. It is part of the SCF (Skp1, Cullin 1, F-box protein) complex, the largest class of sophisticated ubiquitin-proteasome/E3 ligases, and can directly interact with Fbxo7, a gene defective in PARK15-linked PD. In vitro target validation by viral-mediated RNA interference revealed that the deficiency of Skp1 in a mouse SN-derived DAergic neuronal cell line potentiated the damage caused by exogenous insults implicated in PD pathology and caused the death of neurons undergoing differentiation, which developed Lewy body-like, α-synuclein-positive inclusions preceding cell death. Furthermore, recent animal studies show that site-directed intranigral stereotaxic injections of lentiviruses targeting SKP1A induce pathological and behavioral deficits in mice, supporting a significant role of Skp1 in SN DAergic neuronal survival in SPD. Thus, strategies aimed at increasing the activity or content of Skp1 may represent a novel therapeutic approach that has the potential to treat PD.
Eve Topf Center for Neurodegenerative Diseases Research and Department of Molecular Pharmacology, Faculty of Medicine, Technion, Haifa, Israel. mandel@tx.technion.ac.il
Silvia A
SA
Mandel
Tali
T
Fishman-Jacob
Moussa B H
MB
Youdim
D000818:Animals; D059290:Dopaminergic Neurons / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D010300:Parkinson Disease / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D013378:Substantia Nigra / Q000201:enzymology* / Q000473:pathology
D047908:Intracellular Signaling Peptides and Proteins; C493170:TRIB1 protein, human; D017346:Protein Serine-Threonine Kinases