Abstract
BackgroundParkinson’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 of α-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 of α-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 of α-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 cerebral α-synuclein deposition.MethodsIntestinal and olfactory functions, intestine and brain α-synuclein deposition as well as striatal alterations, were assessed in c-rel-/- and control mice from 2 to 18 months of age.ResultsFrom 2 months of age, c-rel-/- mice displayed intestinal constipation and increasing olfactory impairment. At 2 months, c-rel-/- mice exhibited a mild α-synuclein accumulation in the distal colon. Moreover, they developed an age-dependent deposition of fibrillary α-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, the α-synuclein pathology associated with a drop of dopamine transporter in the striatum that anticipated by 6 months the axonal degeneration. From 12 months onwards oxidative/nitrosative stress developed in the striatum in parallel with altered expression of mitochondrial homeostasis regulators in the substantia nigra.ConclusionsIn c-rel-/- mice, reproducing a parkinsonian progressive pathology with non-motor and motor symptoms, a Braak-like pattern of brain ascending α-synuclein deposition occurs. The peculiar phenotype of c-rel-/- mice envisages a potential contribution of c-Rel dysregulation to the pathogenesis of PD.
Highlights
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 of α-synuclein
Studies are currently ongoing by our group to probe this hypothesis. It remains to be determined how exactly the constitutive c-Rel deficiency can induce progressive α-synuclein accumulation and loss of dopaminergic neurons in Substantia nigra (SN) [13], we found that c-rel-/- mice exhibited changes in the expression of proteins controlling mitochondrial homeostasis (PGC1α and B-cell lymphoma-extra large (Bcl-xL)) [32, 66, 67], reactive oxygen species (ROS) generation (UCP4 and uncoupling protein 5 (UCP5)) [31, 68] and ROS scavenging (MnSOD) [69, 70]
Our results indicate that c-rel-/- mice represent a unique mouse model exploitable to study pathogenic mechanisms contributing to the onset of PD, or test the efficacy of therapeutic approaches at PD premotor stages
Summary
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 of α-synuclein. According to the Braak staging, the onset of non-motor and motor symptoms relates to progressive ascendant diffusion of α-synuclein pathology in the brain. It is widely assumed that brain α-synuclein deposition is central to PD pathogenesis This was supported by Braak and collaborators that, from the analysis of post-mortem PD patients’ brains at different disease stages, proposed a correlation between the progression of symptoms and the topographical pattern of LB diffusion [6,7,8,9]. In stage 1, α-synuclein pathology is confined to the DMV as well as olfactory structures and affected subjects exhibit non-motor symptoms such as hyposmia and constipation [10]. At stages 5 and 6, when the cognitive disturbances may occur [10], α-synuclein pathology affects temporal mesocortex and neocortical areas, respectively
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