SLC30A10 Mutation Involved in Parkinsonism Results in Manganese Accumulation within Nanovesicles of the Golgi Apparatus.
SLC30A10 Mutation Involved in Parkinsonism Results in Manganese Accumulation within Nanovesicles of the Golgi Apparatus.
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DOI：
10.1021/acschemneuro.8b00451
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发表时间：
2019-01-16
影响因子：
5
通讯作者：
Ortega R
中科院分区：
文献类型：
--
作者：
Carmona A;Zogzas CE;Roudeau S;Porcaro F;Garrevoet J;Spiers KM;Salomé M;Cloetens P;Mukhopadhyay S;Ortega R
锰（Mn）是一种必需的金属，当暴露量增加时可能具有神经毒性，导致帕金森样综合征。在家族性帕金森综合征的新形式中已经鉴定出Slc 30 a10基因的突变。SLC 30 A10是参与Mn外排的细胞表面蛋白，保护细胞免受Mn毒性。致病突变阻断SLC 30 A10的外排活性，导致Mn积累。确定细胞内定位的锰时，致病SLC 30 A10突变体的表达是必不可少的，以阐明锰神经毒性的机制。在这里，使用细胞器荧光显微镜和同步加速器X射线荧光（SXRF）成像，我们发现在生理条件下和暴露于Mn后，Mn在用致病SLC 30 A10-Δ105-107突变体转染的人细胞的高尔基体中积累。在表达野生型SLC 30 A10蛋白的细胞中，在所有暴露条件后，细胞Mn含量低，证实了有效的Mn流出。在不表达内源性SLC 30 A10的未转染细胞和模拟转染细胞中，Mn位于高尔基体中，类似于其在表达突变蛋白的细胞中的分布，证实Mn流出不足。新开发的SXRF低温纳米成像（<50 nm分辨率）表明，Mn被困在高尔基体内的单个囊泡中。我们的结果证实了SLC 30 A10在表达引起疾病的SLC 30 A10-Δ105-107突变的细胞中Mn流出和Mn积累中的作用。此外，我们确定了亚细胞器高尔基体纳米囊泡作为SLC 30 A10突变体中Mn积累的主要隔室，这表明与囊泡运输机制的相互作用是疾病的原因。
Manganese (Mn) is an essential metal that can be neurotoxic when elevated exposition occurs leading to parkinsonian-like syndromes. Mutations in the Slc30a10 gene have been identified in new forms of familial parkinsonism. SLC30A10 is a cell surface protein involved in the efflux of Mn protecting the cell against Mn toxicity. Disease causing mutations block the efflux activity of SLC30A10, resulting in Mn accumulation. Determining the intracellular localization of Mn when disease-causing SLC30A10 mutants are expressed is essential to elucidate the mechanisms of Mn neurotoxicity. Here, using organelle fluorescence microscopy and synchrotron X-ray fluorescence (SXRF) imaging we found that Mn accumulates in the Golgi apparatus of human cells transfected with the disease-causing SLC30A10-Δ105-107 mutant under physiological conditions and after exposure to Mn. In cells expressing the wild-type SLC30A10 protein, cellular Mn content was low after all exposure conditions, confirming efficient Mn efflux. In non-transfected cells that do not express endogenous SLC30A10, and in mock transfected cells, Mn was located in the Golgi apparatus, similarly to its distribution in cells expressing the mutant protein, confirming deficient Mn efflux. The newly developed SXRF cryogenic nano-imaging (<50 nm resolution) indicated that Mn was trapped in single vesicles within the Golgi apparatus. Our results confirm the role of SLC30A10 in Mn efflux and the accumulation of Mn in cells expressing the disease causing SLC30A10-Δ105-107 mutation. Moreover, we identified sub-organelle Golgi nano-vesicles as the main compartment of Mn accumulation in SLC30A10 mutants suggesting interactions with the vesicular trafficking machinery as a cause of the disease.
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影响因子：
4.7
作者：
Dučić T;Barski E;Salome M;Koch JC;Bähr M;Lingor P
通讯作者：
Lingor P
影响因子：
3.4
作者：
Mukhopadhyay S
通讯作者：
Mukhopadhyay S
影响因子：
3.3
作者：
Mukhopadhyay S;Bachert C;Smith DR;Linstedt AD
通讯作者：
Linstedt AD
影响因子：
3.5
作者：
Leitch, Sharon;Feng, Mingye;Muend, Sabina;Braiterman, Lelita T.;Hubbard, Ann L.;Rao, Rajini
通讯作者：
Rao, Rajini
影响因子：
1.2
作者：
Matsuyama, S.;Shimura, M.;Yamauchi, K.
通讯作者：
Yamauchi, K.