Manganese induces the overexpression of α-synuclein in PC12 cells via ERK activation

Cai, Tongjian; Yao, Ting; Zheng, Gang; Chen, Yaoming; Du, Kang; Cao, Yunxin; Shen, Xuefeng; Chen, Jingyuan; Luo, Wenjing

doi:10.1016/j.brainres.2010.08.055

Cited by 61 publications

(51 citation statements)

References 34 publications

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“…Consistent with these mechanisms, we found that expression of ATP13A2 suppressed Mn 2ϩ -induced cytotoxicity and inhibited cytochrome c release. Furthermore, manganese exposure induces ␣-synuclein expression in cell lines (51,52) and triggers structural transformation, aggregation, and fibrillation of ␣-synuclein in vitro (53). A previous study suggested that overexpression of ATP13A2 suppresses the cytotoxicity of ␣-synuclein in yeast, C. elegans, and rat dopaminergic neurons (10).…”

Section: Discussionmentioning

confidence: 97%

Regulation of Intracellular Manganese Homeostasis by Kufor-Rakeb Syndrome-associated ATP13A2 Protein

Tan

Zhang

Jiang

et al. 2011

Journal of Biological Chemistry

136

135

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Mutations in the ATP13A2 gene are associated with KuforRakeb syndrome (KRS) and are found also in patients with various other types of parkinsonism. ATP13A2 encodes a predicted lysosomal P5-type ATPase that plays important roles in regulating cation homeostasis. Disturbance of cation homeostasis in brains is indicated in Parkinson disease pathogenesis. In this study, we explored the biological function of ATP13A2 as well as the pathogenic mechanism of KRS pathogenic ATP13A2 mutants. The results revealed that wild-type ATP13A2, but not the KRS pathogenic ATP13A2 mutants, protected cells from Mn 2؉ -induced cell death in mammalian cell lines and primary rat neuronal cultures. In addition, wild-type ATP13A2 reduced intracellular manganese concentrations and prevented cytochrome c release from mitochondria compared with the pathogenic mutants. Furthermore, endogenous ATP13A2 was up-regulated upon Mn 2؉ treatment. Our results suggest that ATP13A2 plays important roles in protecting cells against manganese cytotoxicity via regulating intracellular manganese homeostasis. The study provides a potential mechanism of KRS and parkinsonism pathogenesis.Mutations in ATP13A2 were initially identified in patients with Kufor-Rakeb syndrome (KRS), 2 an atypical form of inherited parkinsonism. KRS is characterized by juvenile-onset autosomal recessive nigro-striatal-pallidal-pyramidal neurodegeneration with clinical features of Parkinson disease (PD) plus spasticity, supranuclear upgaze paresis, and dementia (1). Homozygous and heterozygous mutations in ATP13A2 are also found in patients with various parkinsonism, including juvenile parkinsonism, young-onset PD, early-onset PD, and familial PD (2-9). ATP13A2 encodes a predicted lysosomal P5-type cationtransporting ATPase with multiple transmembrane domains. It is highly expressed in the brain, especially in the substantia nigra, the region with characteristic dopaminergic neuronal loss in PD. Ypk9, a yeast ortholog of ATP13A2, was shown to function as a manganese transporter to protect cells from excess Mn 2ϩ exposure, whereas loss of Ypk9 increases the sensitivity of yeast to Mn 2ϩ toxicity (10, 11). Previous studies have suggested that cation disturbance is involved in pathogenesis of PD neurodegeneration. Increased levels of cations, including iron and aluminum, are found in the substantial nigra of the PD patient brain (12, 13). Chronic occupational exposure to copper and/or manganese is associated with higher incidence of PD in a case-control study (14). Furthermore, excess levels of Mn 2ϩ accumulation in brains associated with occupational exposure, psychostimulant drug abuse, and liver disease result in an atypical form of parkinsonism in human (15).PD and parkinsonism are believed to be consequences of interactions between both genetic and environmental components (16,17). In this study, we aimed to explore the connection between the KRS-associated ATP13A2 genetic defect and manganese-associated toxicity. Our results show that wild-type ATP13A2 (ATP13A2WT), but not KRS-as...

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Section: Discussionmentioning

confidence: 97%

Regulation of Intracellular Manganese Homeostasis by Kufor-Rakeb Syndrome-associated ATP13A2 Protein

Tan

Zhang

Jiang

et al. 2011

Journal of Biological Chemistry

136

135

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“…177 In PC12 cells, Mn exposure was similarly found to induce overexpression of a-synuclein while siRNA knockdown of a-synuclein reversed Mn-induced cytotoxicity. 178 Additionally, Mn induced the activation of ERK1/2 in PC12 cells, whereas the MEK1 inhibitor, PD98059, which inhibits the activation of ERK, attenuated both the overexpression of a-synuclein and cytotoxicity. Mn-induced oxidative neuronal damage and a-synuclein oligomerization was also shown to be partially alleviated by pretreatment with reduced glutathione and aggravated by H 2 O 2 pretreatment.…”

Section: A-synucleinmentioning

confidence: 97%

Mutual Neurotoxic Mechanisms Controlling Manganism and Parkisonism

Roth¹

2014

Manganese in Health and Disease

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The studies presented in this review attempt to characterize the functional properties of genes identified as producing Parkinson's disease or Parkinson-like disorders and how mutation of these genes correlate, from a mechanistic perspective, to provocation of manganese (Mn) toxicity. These include genes associated with early-onset of Parkinson's disease, which are comprised of parkin, DJ-1, PINK, and ATP13A2, as well as those associated with late onset of the disorder, which include LRRK2 and VPS35. Because both neurological disorders are associated with altered function and output of the basal ganglia, it is not surprising that symptoms of Parkinson's disease often overlap with that of Mn toxicity. There appears to be four common threads linking the two disorders because mutations in genes associated with early and late onset of Parkinsonism produce similar adverse biological responses acknowledged to provoke Mn-induced dopaminergic cell death: (1) disruption of mitochondrial function leading to oxidative stress; (2) abnormalities in vesicle processing; (3) altered proteasomal and lysosomal protein degradation; and (4) α-synuclein aggregation. The mutual neurotoxic actions of these genes, along with that of Mn, most likely act in synchrony to contribute to the severity, characteristics, and onset of both disorders.

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“…The deposition of this small protein in Lewy bodies due to three point mutations in the a-synuclein gene is a molecular hallmark of familial PD (Ulmer and Bax 2005). It has been reported that Mn can induce overexpression of a-synuclein in PC12 cells, which reduces cellular viability (Cai et al 2010). Furthermore, Mn exposure in rat-derived primary cerebellar neuron culture increased levels of a-synuclein associated to increased oxidative stress (Tong et al 2009).…”

Section: Studies In Rodentsmentioning

confidence: 99%