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

ABSTRACT:

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 of ?-synuclein. We reported that mice deficient for NF-?B/c-Rel (c-rel^-/-) develop a late-onset parkinsonism. At 18 months of age, c-rel^-/- mice showed nigrostriatal degeneration and accumulation of ?-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 ?-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 ?-synuclein deposition.

Methods

Intestinal and olfactory functions, intestine and brain ?-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 mild ?-synuclein accumulation in the distal colon. Moreover, they developed an age-dependent deposition of fibrillary ?-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 ?-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.

Conclusions

In c-rel^-/- mice, reproducing a parkinsonian progressive pathology with non-motor and motor symptoms, a Braak-like pattern of brain ascending ?-synuclein deposition occurs. The peculiar phenotype of c-rel^-/- mice envisages a potential contribution of c-Rel dysregulation to the pathogenesis of PD.

SUBMITTER: Parrella E 

PROVIDER: S-EPMC6530198 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature