Leyva-Illades Dinorah, Chen Pan, Zogzas Charles E, Hutchens Steven, Mercado Jonathan M, Swaim Caleb D, Morrisett Richard A, Bowman Aaron B, Aschner Michael, Mukhopadhyay Somshuvra
Division of Pharmacology and Toxicology, College of Pharmacy, Institutes for Cellular and Molecular Biology and for Neuroscience, University of Texas at Austin, Austin, Texas 78701.
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, and.
J Neurosci. 2014 Oct 15;34(42):14079-95. doi: 10.1523/JNEUROSCI.2329-14.2014.
Manganese (Mn) is an essential metal, but elevated cellular levels are toxic and may lead to the development of an irreversible parkinsonian-like syndrome that has no treatment. Mn-induced parkinsonism generally occurs as a result of exposure to elevated Mn levels in occupational or environmental settings. Additionally, patients with compromised liver function attributable to diseases, such as cirrhosis, fail to excrete Mn and may develop Mn-induced parkinsonism in the absence of exposure to elevated Mn. Recently, a new form of familial parkinsonism was reported to occur as a result of mutations in SLC30A10. The cellular function of SLC30A10 and the mechanisms by which mutations in this protein cause parkinsonism are unclear. Here, using a combination of mechanistic and functional studies in cell culture, Caenorhabditis elegans, and primary midbrain neurons, we show that SLC30A10 is a cell surface-localized Mn efflux transporter that reduces cellular Mn levels and protects against Mn-induced toxicity. Importantly, mutations in SLC30A10 that cause familial parkinsonism blocked the ability of the transporter to traffic to the cell surface and to mediate Mn efflux. Although expression of disease-causing SLC30A10 mutations were not deleterious by themselves, neurons and worms expressing these mutants exhibited enhanced sensitivity to Mn toxicity. Our results provide novel insights into the mechanisms involved in the onset of a familial form of parkinsonism and highlight the possibility of using enhanced Mn efflux as a therapeutic strategy for the potential management of Mn-induced parkinsonism, including that occurring as a result of mutations in SLC30A10.
锰（Mn）是一种必需金属，但细胞内锰水平升高具有毒性，可能导致不可逆的帕金森氏症样综合征，且该病症无有效治疗方法。锰诱导的帕金森症通常是由于在职业或环境环境中接触到升高的锰水平所致。此外，因肝硬化等疾病导致肝功能受损的患者无法排出锰，在未接触升高的锰的情况下也可能发展为锰诱导的帕金森症。最近，据报道一种新的家族性帕金森症是由SLC30A10基因突变引起的。SLC30A10的细胞功能以及该蛋白突变导致帕金森症的机制尚不清楚。在这里，我们结合细胞培养、秀丽隐杆线虫和原代中脑神经元的机制和功能研究表明，SLC30A10是一种细胞表面定位的锰外流转运蛋白，可降低细胞内锰水平并防止锰诱导的毒性。重要的是，导致家族性帕金森症的SLC30A10突变阻碍了转运蛋白转运到细胞表面并介导锰外流的能力。尽管致病的SLC30A10突变本身并无有害影响，但表达这些突变体的神经元和线虫对锰毒性表现出增强的敏感性。我们的结果为家族性帕金森症发病机制提供了新的见解，并强调了利用增强锰外流作为治疗策略来潜在管理锰诱导的帕金森症的可能性，包括由SLC30A10突变引起的帕金森症。
