title: RING finger protein 11 (RNF11) modulates susceptibility to 6-OHDA-induced nigral degeneration and behavioral deficits through NF-κB signaling in dopaminergic cells.
abstract: Chronic activation of the NF-κB pathway is associated with progressive neurodegeneration in Parkinson's disease (PD). Given the role of neuronal RING finger protein 11 (RNF11) as a negative regulator of the NF-κB pathway, in this report we investigated the function of RNF11 in dopaminergic cells in PD-associated neurodegeneration. We found that RNF11 knockdown in an in vitro model of PD mediated protection against 6-OHDA-induced toxicity. In converse, over-expression of RNF11 enhanced 6-OHDA-induced dopaminergic cell death. Furthermore, by directly manipulating NF-κB signaling, we showed that the observed RNF11-enhanced 6-OHDA toxicity is mediated through inhibition of NF-κB-dependent transcription of TNF-α, antioxidants GSS and SOD1, and anti-apoptotic factor BCL2. Experiments in an in vivo 6-OHDA rat model of PD recapitulated the in vitro results. In vivo targeted RNF11 over-expression in nigral neurons enhanced 6-OHDA toxicity, as evident by increased amphetamine-induced rotations and loss of nigral dopaminergic neurons as compared to controls. This enhanced toxicity was coupled with the downregulation of NF-κB transcribed GSS, SOD1, BCL2, and neurotrophic factor BDNF mRNA levels, in addition to decreased TNF-α mRNA levels in ventral mesenchephalon samples. In converse, knockdown of RNF11 was associated with protective phenotypes and increased expression of above-mentioned NF-κB transcribed genes. Collectively, our in vitro and in vivo data suggest that RNF11-mediated inhibition of NF-κB in dopaminergic cells exaggerates 6-OHDA toxicity by inhibiting neuroprotective responses while loss of RNF11 inhibition on NF-κB activity promotes neuronal survival. The decreased expression of RNF11 in surviving cortical and nigral tissue detected in PD patients, thus implies a compensatory response in the diseased brain to PD-associated insults. In summary, our findings demonstrate that RNF11 in neurons can modulate susceptibility to 6-OHDA toxicity through NF-κB mediated responses. This neuron-specific role of RNF11 in the brain has important implications for targeted therapeutics aimed at preventing neurodegeneration.
authors: Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA. epranski@gmail.com
authors: Elaine L
authors: EL
authors: Pranski
authors: Nirjari V
authors: NV
authors: Dalal
authors: Carson Van
authors: CV
authors: Sanford
authors: Jeremy H
authors: JH
authors: Herskowitz
authors: Marla
authors: M
authors: Gearing
authors: Carlos
authors: C
authors: Lazo
authors: Gary W
authors: GW
authors: Miller
authors: James J
authors: JJ
authors: Lah
authors: Allan I
authors: AI
authors: Levey
authors: Ranjita S
authors: RS
authors: Betarbet
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins; D059290:Dopaminergic Neurons / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology; D014162:Transfection
chemical_list: D018663:Adrenergic Agents; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D016328:NF-kappa B; C404508:RNF11 protein, human; D016627:Oxidopamine