ATP13A2 (PARK9) polymorphisms influence the neurotoxic effects of manganese

Rentschler, Gerda; Covolo, Loredana; Haddad, Amelia Ahmadi; Lucchini, Roberto; Zoni, Silvia; Broberg, Karin

doi:10.1016/j.neuro.2012.01.007

Cited by 55 publications

(47 citation statements)

References 37 publications

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“…For example, deterioration in motor function is proportional to the levels of Mn found in the soil of various geochemical provinces [18]. Likewise, an increase in Mn in the brains of professional welders leads to a quicker development of Parkinson's disease [19,20].…”

Section: Discussionmentioning

confidence: 99%

Nasal aerodynamics protects brain and lung from inhaled dust in subterranean diggers,Ellobius talpinus

et al. 2014

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Inhalation of air-dispersed sub-micrometre and nano-sized particles presents a risk factor for animal and human health. Here, we show that nasal aerodynamics plays a pivotal role in the protection of the subterranean mole vole Ellobius talpinus from an increased exposure to nano-aerosols. Quantitative simulation of particle flow has shown that their deposition on the total surface of the nasal cavity is higher in the mole vole than in a terrestrial rodent Mus musculus (mouse), but lower on the olfactory epithelium. In agreement with simulation results, we found a reduced accumulation of manganese in olfactory bulbs of mole voles in comparison with mice after the inhalation of nano-sized MnCl 2 aerosols. We ruled out the possibility that this reduction is owing to a lower transportation from epithelium to brain in the mole vole as intranasal instillations of MnCl 2 solution and hydrated nanoparticles of manganese oxide MnO . (H 2 O) x revealed similar uptake rates for both species. Together, we conclude that nasal geometry contributes to the protection of brain and lung from accumulation of air-dispersed particles in mole voles.

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Section: Discussionmentioning

confidence: 99%

Nasal aerodynamics protects brain and lung from inhaled dust in subterranean diggers,Ellobius talpinus

et al. 2014

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“…The rs2871776 G allele that was associated with an adverse effect of Mn on motor coordination was associated with destroying a binding site for the transcription factor INSM1 that plays an important role in developing the central nervous system as shown in mouse and human embryos [72][73][74]. Absence of the binding site for this transcription factor on ATP13A2 hypothetically might explain why adult carriers in our study population perform more poorly in the motor coordination test upon Mn exposure [71]. The effect of Mn exposure on the nervous system was, in the elderly, influenced by the genetic polymorphism of PARK9, a susceptible gene for PD [71].…”

Section: Park2 Atp13a2 (Park9)mentioning

confidence: 71%

“…None of the polymorphisms alone had a significant influence on the motor coordination. After combination with Mn exposure, the rs4920608 CT and CC carriers showed decreased motor coordination, compared with TT carriers [71]. In addition, motor coordination was also reduced in the rs2871776-GG and -GA carriers, compared with the AA individuals with increasing of Mn exposure [71].…”

Section: Park2 Atp13a2 (Park9)mentioning

confidence: 89%

“…Particularly, the genetic polymorphisms of the ATP13A2 influence both PD and Mn toxicity [70]. The SNPs as intron variants, rs4920608 and rs2871776, significantly modified the effects of Mn exposure on the impaired motor coordination in the elderly (p = 0.029 and p = 0.041, respectively), also after adjustments for age and gender (p = 0.032 and p = 0.044) [71]. In addition, the rs2871776 G allele that was associated with the worst effect of Mn on motor coordination was linked to alteration of a binding site for the transcription factor Insulinoma-associated 1 (INSM1) [70].…”

Section: Park2 Atp13a2 (Park9)mentioning

confidence: 99%

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A Current Review for Biological Monitoring of Manganese with Exposure, Susceptibility, and Response Biomarkers

Kim

Lee

Bang

et al. 2015

Journal of Environmental Science and Health, Part C

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People can be easily exposed to manganese (Mn), the twelfth most abundant element, through various exposure routes. However, overexposure to Mn causes manganism, a motor syndrome similar to Parkinson disease, via interference of the several neurotransmitter systems, particularly the dopaminergic system in areas. At cellular levels, Mn preferentially accumulates in mitochondria and increases the generation of reactive oxygen species, which changes expression and activity of manganoproteins. Many studies have provided invaluable insights into the causes, effects, and mechanisms of the Mn-induced neurotoxicity. To regulate Mn exposure, many countries have performed biological monitoring of Mn with three major biomarkers: exposure, susceptibility, and response biomarkers. In this study, we review current statuses of Mn exposure via various exposure routes including food, high susceptible population, effects of genetic polymorphisms of metabolic enzymes or transporters (CYP2D6, PARK9, SLC30A10, etc.), alterations of the Mn-responsive proteins (i.e., glutamine synthetase, Mn-SOD, metallothioneins, and divalent metal trnsporter1), and epigenetic changes due to the Mn exposure. To minimize the effects of Mn exposure, further biological monitoring of Mn should be done with more sensitive and selective biomarkers.

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“…Supporting this is a recent study implicating ATP13A2 variants as potential risk factors for the neurotoxic actions of Mn in humans. 121 Based on the overall findings in the literature, ATP13A2 stimulation of Mn toxicity is likely to involve intracellular vesicular cation transport processes, which have the potential to indirectly provoke oxidative stress signals. Since ATP13A2 is selectively localized to the substantia nigra dopaminergic neurons, the actions of the variants will have little direct impact on Mn activity in the globus pallidus, at least in regard to its neurotic actions.…”

Section: Atp13a2mentioning

confidence: 99%

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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ATP13A2 (PARK9) polymorphisms influence the neurotoxic effects of manganese

Cited by 55 publications

References 37 publications

Nasal aerodynamics protects brain and lung from inhaled dust in subterranean diggers,Ellobius talpinus

Nasal aerodynamics protects brain and lung from inhaled dust in subterranean diggers,Ellobius talpinus

A Current Review for Biological Monitoring of Manganese with Exposure, Susceptibility, and Response Biomarkers

Mutual Neurotoxic Mechanisms Controlling Manganism and Parkisonism

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