Down-regulation of LRRK2 in control and DAT transfected HEK cells increases manganese-induced oxidative stress and cell toxicity

Roth, Jerome A.; Eichhorn, Michelle

doi:10.1016/j.neuro.2013.04.008

Cited by 11 publications

(3 citation statements)

References 62 publications

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“…What is most significant is the observation that Mn stimulates phosphorylation activity of the G2019S mutant protein, whereas it inhibits wild-type kinase activity normally activated by Mg. 151,152 Recent studies have confirmed that when LRRK2 is silenced with an shRNA, Mn can potentiate oxidative stress, leading to cell death as indicated by activation of both ROS and JNK. 153 In contrast, Mn was shown to reduced phosphorylation of p38, consistent with the fact that p38 is a likely a downstream substrate of LRRK2. 154 Unlike the other genes associated with Mn toxicity, LRRK2 is an autosomal dominant gene and therefore potentially differentiates a population of individuals that, upon exposure to excess Mn, can develop early symptoms of manganism even in the absence of overt signs of Parkinson's disease.…”

Section: Lrrk2mentioning

confidence: 56%

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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Section: Lrrk2mentioning

confidence: 56%

Mutual Neurotoxic Mechanisms Controlling Manganism and Parkisonism

Roth¹

2014

Manganese in Health and Disease

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“…This effect was induced by the Rb in the MWCNT supernatant. Some metals are known to produce reactive oxygen species (Ding et al, 2008) that can result in oxidative stress on lipids, DNA and proteins (Henriksson and Tjalve, 2000;Choi et al, 2007;Alekseenko et al, 2008;Kim et al, 2011;Latronico et al, 2013;Roth and Eichhorn, 2013;Sripetchwandee et al, 2013). Thus, we examined the involvement of ROS in the suppression of NSC proliferation.…”

Section: Resultsmentioning

confidence: 99%

Residual metals in carbon nanotubes suppress the proliferation of neural stem cells

Shigemoto-Mogami¹,

Fujimori

Ikarashi

et al. 2014

Fundam. Toxicol. Sci.

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Carbon nanotubes (CNTs) are used in many fields; however, little is known about the effects of CNTs on the central nervous system (CNS). In this study, we found that extracts of sonicated CNTs suppressed the proliferation of neural stem cells (NSCs). Single-walled CNTs (SWCNTs) and multiple-walled CNTs (MWCNTs) were suspended in PBS (1 mg/mL) and sonicated for 5 hr using a water bath sonicator. Supernatants from both types of CNTs suppressed NSC proliferation. The effects weakened in a dilution-ratio-dependent manner and strengthened in a sonication time-dependent manner. Metal concentrations extracted from SCNTs and MCNTs after 5-hr of sonication were determined using inductively coupled plasma mass spectrometry. Mn, Rb, Cs, Tl, and Fe were detected in the SWCNT supernatant, and Mn, Cs, W, and Tl were detected in the MWCNT supernatant. The concentration of Mn, Rb, and Fe eluted from the SWCNTs and Rb eluted from MWCNTs following sonication were sufficient to suppress NSC proliferation alone. N-acetyl cysteine (NAC) and ascorbic acid (AA) reversed the effects of Mn and Fe and restored NSC proliferation. The effects of Rb and Tl were not affected by the antioxidants. Both antioxidants largely restored the suppression of NSC proliferation induced by the SWCNT and MWCNT supernatants. These results suggest that metals extracted from CNTs via a strong vibration energy can suppress NSC proliferation through ROS production by the extracted metals.

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“…Interestingly, G2019S mutation of LRRK2 enhanced KIN domain-Mn interactions, prolonging and increasing LRRK2 kinase activity [142]. In contradiction to these findings, studies showed that Mn-induced oxidative stress and neurotoxicity are exacerbated after LRRK2 downregulation in HEK293 cells, suggesting a protective role of LRRK2 in Mn toxicity [143]. These findings indicate that Mn toxicity may involve alterations in the kinase activity of LRRK2 and its regulation of the autophagy-lysosomal pathway, warranting further exploration of the gene-environmental interaction in pathogenic PTMs.…”

Section: Lrrk2mentioning

confidence: 99%

The role of posttranslational modifications of α-synuclein and LRRK2 in Parkinson's disease: Potential contributions of environmental factors

Pajarillo

Rizor

Lee

et al. 2019

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease (AD), and the most prevalent movement disorder. PD is characterized by dopaminergic neurodegeneration in the substantia nigra, but its etiology has yet to be established. Among several genetic variants contributing to PD pathogenesis, α-synuclein and leucine-rich repeat kinase (LRRK2) are widely associated with neuropathological phenotypes in familial and sporadic PD. α-Synuclein and LRRK2 found in Lewy bodies, a pathogenetic hallmark of PD, are often posttranslationally modified. As posttranslational modifications (PTMs) are key processes in regulating the stability, localization, and function of proteins, PTMs have emerged as important modulators of pathogenic mechanisms of α-synuclein and LRRK2. Aberrant PTMs altering phosphorylation, ubiquitination, nitration and truncation of these proteins promote PD pathogenesis, while other PTMs such as sumoylation may be protective. Although the causes of many aberrant PTMs are unknown, environmental risk factors may contribute to their aberrancy. Environmental toxicants such as rotenone and paraquat have been shown to interact with these proteins and promote their abnormal PTMs. Notably, manganese (Mn) exposure leads to PD-like neurological disorder referred to as manganism—and induces pathogenic PTMs of α-synuclein and LRRK2. In this review, we highlight the role of PTMs of LRRK2 and α-synuclein in PD pathogenesis and discuss the impact of environmental risk factors on their aberrancy.

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Down-regulation of LRRK2 in control and DAT transfected HEK cells increases manganese-induced oxidative stress and cell toxicity

Cited by 11 publications

References 62 publications

Mutual Neurotoxic Mechanisms Controlling Manganism and Parkisonism

Mutual Neurotoxic Mechanisms Controlling Manganism and Parkisonism

Residual metals in carbon nanotubes suppress the proliferation of neural stem cells

The role of posttranslational modifications of α-synuclein and LRRK2 in Parkinson's disease: Potential contributions of environmental factors

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