Sex-related differences in phenotype and nigro-striatal degeneration of c-rel-/- mouse model of Parkinson’s disease

Background: Sex is an important factor in the development and symptom expression of Parkinson’s disease (PD). Risk of developing PD, motor and non-motor symptoms and response to treatment differ between men and women, with women showing lower disease incidence, later onset of motor deficits and generally milder symptoms than men. We previously reported that male mice lacking the NF-κB/c-Rel protein (c-rel-/- mice) undergo age-related accumulation of α-synuclein, and loss of dopaminergic neurons, in the substantia nigra (SN). In addition, c-rel-/- male mice present a progressive PD-like phenotype characterized by both motor deficits and non-motor symptoms (such as constipation, hyposmia, anxiety, depressive-like behavior and apathy). In this study, we give evidence that female mice reproduce only part of the parkinsonian pathology and do not show behavioral manifestations. Methods: Nigro-striatal alterations as well as motor and non-motor symptoms were assessed in aged c-rel-/- and wild-type (wt) male and female mice through histological techniques and behavioral tests. Results: Likewise c-rel-/- males, c-rel-/- females displayed significant reduction of dopaminergic neurons in the SN at 18 months of age, but only minor reduction of striatal TH-positive (TH+) and DAT-positive (DAT+) dopaminergic fibers compared to wt littermates. Besides, c-rel-/- females did not develop significant motor deficits and non-motor symptoms, as constipation, hyposmia, depressive-like and apathetic behaviors. Conclusions: Our results show that, differently from aged males, c-rel-/- females do not develop a parkinsonian behavior, in line with evidence from the human PD. The phenotype mice display a nigral dopaminergic neuron degeneration but conserved nigrostriatal fiber density. The degeneration and PD-like symptoms are compatible with the sex-related differences on incidence and symptoms progression observed in PD patients.