Objective: The aim of the present study was to investigate whether the nigro-striatal system in a genetic mouse model of primary familial brain calcification (PFBC) is more susceptible to dopaminergic toxins.

Background: Primary familial brain calcification (PFBC) is characterized by calcifications in the basal ganglia and other brain areas. It can be caused by mutations in at least four different dominantly inherited genes, namely SLC20A2, PDGFRB, PDGFB, or XPR1. Calcification of the brain is present in 100% of mutation carriers, whereas associated movement disorders, such as dystonia and parkinsonism, are present in only about 50%. The disease mechanism of calcification and even more importantly, the impact of these calcifications on the development of clinical symptoms, in particular movement disorders, remains unknown.

Methods: To this end, we used PDGFbret/ret mice that develop brain calcifications at the age of 4 months. We analyzed these mice in two different toxin-based PD models to test the integrity of the nigro-striatal system.

Results: First, we treated PDGFbret/ret mice and wild-type (WT) littermates with MPTP. We found increased levels of MPP+ in the brain of PDGFbret/ret mice, which supports the hypothesis that PDGF-B dysfunction leads to pericyte dysfunction and an altered blood brain barrier. Second, we intoxicated 8- and 12- month-old PDGFbret/ret mice and WT controls with a unilateral intrastriatal 6-OHDA injection and analyzed behavior and the integrity of the nigro-striatal system. We found that, although the nigro-striatal pathway is unaffected in aged PDGFbret/ret mice under basal conditions, the toxin-naïve animals showed behavioral alterations that increase between 8 and 12 months of age. After 6-OHDA injection, the nigro-striatal system of 12-month-old mice is more affected compared to controls, which is also reflected on the behavioral level. Again, these differences increased with age.

Conclusions: It is conceivable that the results of the MPTP treatment reflect the situation in humans, i.e. that the concentration of incidentally accumulated environmental toxins is higher in the brains of PDGFB mutation carriers compared to healthy controls. Regardings the results in aged 6-OHDA treated animals, it is tempting to speculate that, despite an alteration in striatal dopamine levels in aged PDGFbret/ret mice, the nigro-striatal system becomes more susceptible to brain damage with an increasing load of calcifications.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/primary-familial-brain-calcification-the-impact-of-calcifications-on-the-development-of-motor-symptoms/