RESUMO
Fas-associated factor 1 or FAF1 is a Fas-binding protein implicated in apoptosis. FAF1 is the product of a gene at PARK 10 locus on chromosome 1p32, a locus associated with late-onset PD [Hicks, A.A., Petursson, H., Jonsson, T., Stefansson, H., Johannsdottir, H.S., Sainz, J., Frigge, M.L.et al., 2002. A susceptibility gene for late-onset idiopathic Parkinson's disease. Ann Neurol. 52, 549-555.]. In the present study we investigated the role of FAF1 in cell death and in Parkinson's disease (PD) pathogenesis. FAF1 levels were significantly increased in frontal cortex of PD as well as in PD cases with Alzheimer's disease (AD) pathology compared to control cases. Changes in FAF1 expression were specific to PD-related alpha-synuclein pathology and nigral cell loss. In addition, PD-related insults including, mitochondrial complex I inhibition, oxidative stress, and increased alpha-synuclein expression specifically increased endogenous FAF1 expression in vitro. Increased FAF1 levels induced cell death and significantly potentiated toxic effects of PD-related stressors including, oxidative stress, mitochondrial complex I inhibition and proteasomal inhibition. These studies, together with previous genetic linkage studies, highlight the potential significance of FAF1 in pathogenesis of idiopathic PD.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Encéfalo/metabolismo , Neurônios/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Idoso , Idoso de 80 Anos ou mais , Proteínas Reguladoras de Apoptose , Encéfalo/patologia , Encéfalo/fisiopatologia , Morte Celular/genética , Linhagem Celular , Cromossomos Humanos Par 1/genética , Complexo I de Transporte de Elétrons/metabolismo , Metabolismo Energético/genética , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Lobo Frontal/fisiopatologia , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Degeneração Neural/genética , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Neurônios/patologia , Estresse Oxidativo/genética , Doença de Parkinson/fisiopatologia , Substância Negra/metabolismo , Substância Negra/patologia , Substância Negra/fisiopatologia , alfa-Sinucleína/metabolismoRESUMO
The PARK10 locus is associated with idiopathic Parkinson disease (PD), but the responsible gene remains to be identified. Genes associated with familial PD, as well as biochemical evidence from sporadic PD and animal models, have implicated components of the ubiquitin-proteasome system in PD pathogenesis. One attractive candidate gene at the PARK10 locus is RING-Finger Protein 11 (RNF11), the deduced amino acid sequence of which predicts a RING-H2 domain common to E3 ubiquitin ligases such as parkin. To facilitate understanding of this protein and its possible role in PD, we characterized the expression and localization of RNF11 in brain. We detected RNF11 transcript and protein and provided the first direct evidence that RNF11 is expressed in brain. Immunohistochemical analysis of RNF11 protein in rat and human brain, using 2 different antibodies, corroborated the mRNA findings. Both antibodies show that RNF11 is restricted to neurons and excluded from white matter. Moreover, RNF11 is expressed by vulnerable neurons of the substantia nigra and sequestered into Lewy bodies in brains of patients with idiopathic PD. Collectively, these findings identify RNF11 as a strong candidate gene at the PARK10 locus and highlight its potential significance in the development of the common form of PD.