J. Neurosci. 34, 14079–14095 (2014)


Exposure to elevated levels of manganese (Mn) or a defect in Mn excretion by the liver can lead to an irreversible parkinsonian-like syndrome that shares some but not all clinical and pathological features with Parkinson's disease. Recent work has identified a gene linked to a familial form of Mn-induced Parkinsonism, SLC30A10, but its cellular function and disease mechanism have been unknown. Leyva-Illades et al. set out to identify the gene product and began by demonstrating its localization at the cell membrane of HeLa cells. Five disease-linked SLC30A10 mutants, including Δ105–107 and L89P, were mislocalized to the endoplasmic reticulum (ER), where they are tagged for proteasomal degradation. The L89P mutant was also ER localized in two different cell types tested in whole Caenorhabditis elegans worms, as was Δ105–107 in a rat neuronal cell line and in mouse primary midbrain neurons. Given clues from its sequence, the authors next tested the metal-transporting ability of SLC30A10. A direct assay of metal transport and pulse chase experiments suggested that SLC30A10, but not the mutants, acts as an efflux transporter to lower cellular Mn levels. SLC30A10 expression protected HeLa cells as well as neurons and worms against Mn-induced toxicity, whereas the Δ105–107 or L89P mutations or SLC30A10 knockdown did not. These results suggest that the Parkinsonism caused by mutation in SLC30A10 is a result of a block in Mn efflux from affected cells.