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

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. 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.

Intestinal 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.

From 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.

In 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.