Table 1.

Evidence of metal transporters involved in Mn homeostasis at the brain barriers.

Protein	Experimental Model	Major Results and Conclusions	Reference
Transferrin (Tf)	Hypotransferrinemic (Hpx) mice as a model for Tf deficiency	▪Hpx mice had normal brain Mn accumulation. ▪Suggests that Tf is not required for brain Mn loading.	[58]
DMT1	Human brain endothelial cells (hBMVEC) as a model for the BBB	▪Increased Mn uptake despite inhibition of clathrin-mediated endocytosis. ▪Suggests that DMT1 and Tf/TfR1 pathway is not necessary for Mn uptake in brain endothelial cells.	[67]
	Belgrade rats as a model for DMT1 deficiency	▪Belgrade rats have normal brain Mn levels. ▪Indicates that DMT1 is not necessary for brain Mn accumulation.	[68]
ZIP8	Choroid plexus epithelial cells (HIBCPP) as a model for the BCB	▪ZIP8 knockdown reduces Mn uptake. ▪ZIP8 is primarily localized to the apical membrane ▪Suggests that ZIP8 may mediate apical Mn uptake into CP epithelial cells.	[73]
	hBMVEC cell model of BBB	▪ZIP8 is expressed on both apical and basolateral membrane. ▪ZIP8 is involved in both apical-to-basolateral and basolateral-to-apical Mn transport.	[67]
ZIP14	HIBCPP cell model of BCB	▪ZIP14 knockdown reduces Mn uptake. ▪ZIP14 is expressed on the basolateral membrane. ▪Suggests that ZIP14 may mediate basolateral Mn transport into CP epithelial cells.	[73]
	hBMVEC cell model of BBB	▪ZIP14 is expressed at both apical and basolateral membrane. ▪ZIP14 is involved in both apical-to-basolateral and basolateral-to-apical Mn transport.	[67]
ZnT10	Pan-neuronal/glial Znt10 knockout (KO) mice as a model for brain ZnT10 deficiency	▪Pan-neuronal/glial Znt10 KO mice have increased Mn accumulation in certain brain areas under Mn overload conditions induced by subcutaneous Mn injection. ▪Suggests reduced Mn efflux from the brain with ZnT10 deficiency when body Mn levels increase.	[78]
ATP13A2	Atp13a2−/− mice as a model for ATP13A2 deficiency	▪Atp13a2−/− mice accumulate more Mn in the brain compared to the control mice after intraperitoneal administration of MnCl2.	[83]
	HeLa cells and C. elegans with ATP13A2 overexpression	▪Overexpression of ATP13A2 protects HeLa cells from Mn-induced cytotoxicity. ▪C. elegans overexpressing ATP13A2 in dopamine neurons are more resistant to Mn-induced neurotoxicity. ▪Suggests that ATP13A2 may have a role in maintaining brain Mn homeostasis.	[84]