NF-κB/c-Rel deficiency causes Parkinson’s disease-like prodromal symptoms and progressive pathology in mice  

作　　者：Edoardo Parrella Arianna Bellucci Vanessa Porrini Marina Benarese Annamaria Lanzillotta Gaia Faustini Francesca Longhena Giulia Abate Daniela Uberti Marina Pizzi 

机构地区：[1]Department of Molecular and Translational Medicine,University of Brescia,Viale Europa 11,25123 Brescia,Italy

出　　处：《Translational Neurodegeneration》2019年第1期183-202,共20页转化神经变性病（英文）

基　　金：This work was funded by Fondazione Cariplo(2014-0769),University of Brescia“BIOMANE”-Health&Wealth project and MIUR PNR 2015-2020 PerMedNet.

摘　　要：Background:Parkinson’s disease(PD),the most common neurodegenerative movement disorder,is characterized by dopaminergic nigrostriatal neuron loss and brain accumulation of Lewy bodies,protein aggregates mainly composed ofα-synuclein.We reported that mice deficient for NF-κB/c-Rel(c-rel^(-/-))develop a late-onset parkinsonism.At 18 months of age,c-rel^(-/-)mice showed nigrostriatal degeneration and accumulation ofα-synuclein aggregates associated with a motor impairment responsive to L-DOPA administration.Being c-Rel protein a transcriptional regulator for mitochondrial anti-oxidant and antiapoptotic factors,it has been inferred that its deficiency may affect the resilience of“energy demanding”nigral dopaminergic neurons to the aging process.PD patients manifest a prodromal syndrome that includes olfactory and gastrointestinal dysfunctions years before the frank degeneration of nigrostriatal neurons and appearance of motor symptoms.According to the Braak staging,the onset of non-motor and motor symptoms relates to progressive ascendant diffusion ofα-synuclein pathology in the brain.The aim of this study was to identify whether c-rel^(-/-)deficiency is associated with the onset of premotor signs of PD and spatio-temporal progression of cerebralα-synuclein deposition.Methods:Intestinal and olfactory functions,intestine and brainα-synuclein deposition as well as striatal alterations,were assessed in c-rel^(-/-)and control mice from 2 to 18 months of age.Results:From 2 months of age,c-rel^(-/-)mice displayed intestinal constipation and increasing olfactory impairment.At 2 months,c-rel^(-/-)mice exhibited a mildα-synuclein accumulation in the distal colon.Moreover,they developed an agedependent deposition of fibrillaryα-synuclein that,starting at 5 months from the olfactory bulbs,dorsal motor nucleus of vagus and locus coeruleus,reached the substantia nigra at 12 months.At this age,theα-synuclein pathology associated with a drop of dopamine transporter in the striatum that anticipated by 6 months the axo

关 键 词：Parkinson’s disease NF-κB/c-Rel non-motor symptoms Α-SYNUCLEIN pathology progression 

分 类 号：R74[医药卫生—神经病学与精神病学]