Jiaqi Zou, MSc, BA: No relevant financial relationship(s) with ineligible companies to disclose.
Objectives: Mutations in SLC39A14, encoding the metal transporter ZIP14, are associated with brain manganese (Mn) overload, Mn neurotoxicity, and childhood-onset parkinsonism, characterized by motor and cognitive deficits. Despite in vitro evidence of ZIP14 expression on the endothelial cells of the blood-brain barrier, its involvement in brain Mn accumulation in vivo remains unexplored. Our objective is to investigate the role of endothelial ZIP14 in brain Mn clearance in vivo and how its absence affects motor and cognition in mice.
Methods: We conducted immunofluorescence staining on brain sections, microvessels, and primary brain endothelial cells to verify ZIP14 expression. We generated an endothelial-specific Zip14 knockout mouse model (EKO). EKO and control mice received Mn supplementation via daily intranasal Mn delivery for 21 days or dietary Mn in drinking water for eight weeks. Tracer 54Mn was administered intranasally and brain 54Mn was measured at steady state and post-supplementation. Motor and cognitive tests were also conducted following supplementation.
Results: We confirmed ZIP14 expression in vivo and ex vivo, with upregulation in response to Mn supplementation. In both steady state and post-supplementation conditions, EKO mice exhibited greater 54Mn retention in the brain compared to controls, indicating a lack of Mn clearance. Post-supplementation motor and cognitive tests revealed unexpected findings. While EKO mice were faster in the crossbeam and static rod tasks of fine motor coordination, they had impaired performance in the novel object recognition task compared to controls.
Conclusions: Our findings highlight ZIP14’s role in brain Mn clearance and its potential as a therapeutic target for reducing brain Mn accumulation and mitigating Mn-induced neurotoxicity. The unexpected behavioral findings emphasize the complexity of Mn homeostasis and neurological function, warranting further investigation into the underlying mechanism.
Funding Sources: Cornell University-Division of Nutritional Sciences
