Recent studies found that mutations in the human SLC30A10 gene, which encodes a manganese (Mn) efflux transporter, are associated with hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC). However, the relationship between Mn metabolism and HMDPC is poorly understood, and no specific treatments are available for this disorder. Here, we generated two zebrafish slc30a10 mutant lines using the CRISPR/Cas9 system. Compared to wild-type animals, mutant adult animals developed significantly higher systemic Mn levels, and Mn accumulated in the brain and liver of mutant embryos in response to exogenous Mn. Interestingly, slc30a10 mutants developed neurological deficits in adulthood, as well as environmental Mn-induced manganism in the embryonic stage; moreover, mutant animals had impaired dopaminergic and GABAergic signaling. Finally, mutant animals developed steatosis, liver fibrosis, and polycythemia accompanied by increased epo expression. This phenotype was rescued partially by EDTA- CaNa 2 chelation therapy and iron supplementation. Interestingly, prior to the onset of slc30a10 expression, expressing ATP2C1 (ATPase secretory pathway Ca 2+ transporting 1) protected mutant embryos from Mn exposure, suggesting a compensatory role for Atp2c1 in the absence of Slc30a10. Notably, expressing either wild-type or mutant forms of SLC30A10 was sufficient to inhibit the effect of ATP2C1 in response to Mn challenge in both zebrafish embryos and HeLa cells. These findings suggest that either activating ATP2C1 or restoring the Mn-induced trafficking of ATP2C1 can reduce Mn accumulation, providing a possible target for treating HMDPC. Author summary Impaired function of the manganese transporter SLC30A10 has been implicated in HMDPC (hypermanganesemia with dystonia, polycythemia, and cirrhosis), an early-onset metabolic disorder clinically characterized by increased systemic Mn levels, neurological impairment, polycythemia, and hepatic injury. No specific treatment is currently available for HMDPC. Moreover, the mechanisms that underlie Mn metabolism are poorly understood, thereby hindering the development of effective treatments. To investigate the physiological processes underlying Mn metabolism and to develop new disease models of HMDPC, we generated two zebrafish slc30a10 mutant lines using the CRISPR/Cas9 system and found that these mutants develop clinical deficits typically associated with HMDPC. Furthermore, we identified a putative compensatory role for ATP2C1 in the absence of SLC30A10 with respect to modulating Mn metabolism. These findings provide a valuable tool for investigating the role of manganese dysregulation in neurological degenerative diseases and which can be used to develop new pharmacological approaches for managing Mn accumulation.
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