Global DNA methylation profiling of manganese-exposed human neuroblastoma SH-SY5Y cells reveals epigenetic alterations in Parkinson’s disease-associated genes

Tarale, Prashant; Sivanesan, Saravanadevi; Daiwile, Atul P.; Stöger, Reinhard; Bafana, Amit; Naoghare, Pravin K.; Parmar, Devendra; Chakrabarti, Tapan; Krishnamurthi, Kannan

doi:10.1007/s00204-016-1899-0

Cited by 45 publications

(27 citation statements)

References 57 publications

(2 reference statements)

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“…Alternatively, or in addition, these lasting protein level changes may be mediated via epigenetic mechanisms, given that expression of several of them (e.g., TH, D2, DAT, and NET) are in part epigenetically regulated via DNA methylation (Archer, Berman, & Blum, ; Day et al, ; Groleau et al, ; Hillemacher et al, ) . This latter suggestion is supported by several studies in human neuroblastoma SH‐SY5Y cells showing that Mn exposure led to hypermethylated TH promoter and down‐regulated TH gene transcription (Gandhi, Sivanesan, & Kannan, ; Tarale et al, ). Recent evidence has also shown that TH expression can be mediated in part by the activity of c‐RET kinase, and that human neuroblastoma cells exposed to 30 µM Mn experienced a c‐RET mediated reduction in TH (Kumasaka et al, ).…”

Section: Discussionmentioning

confidence: 67%

Early postnatal manganese exposure causes arousal dysregulation and lasting hypofunctioning of the prefrontal cortex catecholaminergic systems

Conley

Beaudin

Lasley

et al. 2020

Journal of Neurochemistry

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Studies have reported associations between environmental manganese (Mn) exposure and impaired cognition, attention, impulse control, and fine motor function in children. Our recent rodent studies established that elevated Mn exposure causes these impairments. Here, rats were exposed orally to 0, 25, or 50 mg Mn kg -1 day -1 during early postnatal life (PND 1-21) or lifelong to determine whether early life Mn exposure causes heightened behavioral reactivity in the open field, lasting changes in the catecholaminergic systems in the medial prefrontal cortex (mPFC), altered dendritic spine density, and whether lifelong exposure exacerbates these effects. We also assessed astrocyte reactivity (glial fibrillary acidic protein, GFAP), and astrocyte complement C3 and S100A10 protein levels as markers of A1 proinflammatory or A2 anti-inflammatory reactive astrocytes. Postnatal Mn exposure caused heightened behavioral reactivity during the first 5-10 min intervals of daily open field test sessions, consistent with impairments in arousal regulation. Mn exposure reduced the evoked release of norepinephrine (NE) and caused decreased protein levels of tyrosine hydroxylase (TH), dopamine (DA) and NE transporters, and DA D1 receptors, along with increased DA D2 receptors. Mn also caused a lasting increase in reactive astrocytes (GFAP) exhibiting increased A1 and A2 phenotypes, with a greater induction of the A1 proinflammatory phenotype. These results demonstrate that early life Mn exposure causes broad lasting hypofunctioning of the mPFC catecholaminergic systems, consistent with the impaired arousal regulation, attention, impulse control,and fine motor function reported in these animals, suggesting that mPFC catecholaminergic dysfunction may underlie similar impairments reported in Mn-exposed children.

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Section: Discussionmentioning

confidence: 67%

Early postnatal manganese exposure causes arousal dysregulation and lasting hypofunctioning of the prefrontal cortex catecholaminergic systems

Conley

Beaudin

Lasley

et al. 2020

Journal of Neurochemistry

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“…Regarding PD risk, gene activity of PARK2 and PINK1 was altered via DNA hypermethylation in dopaminergic human neuroblastoma SH-SY5Y cells upon Mn exposure (Tarale et al, 2016). Furthermore, mice exposed to MnCl 2 showed DNA hypo- and hypermethylation of different loci in substantia nigra (Yang et al, 2016).…”

Section: Other Nutritional/environmental Factors and Dna Methylationmentioning

confidence: 99%

Implications of DNA Methylation in Parkinson’s Disease

Miranda-Morales

Meier

Sandoval-Carrillo

et al. 2017

Front. Mol. Neurosci.

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It has been 200 years since Parkinson’s disease (PD) was first described, yet many aspects of its etiopathogenesis remain unclear. PD is a progressive and complex neurodegenerative disorder caused by genetic and environmental factors including aging, nutrition, pesticides and exposure to heavy metals. DNA methylation may be altered in response to some of these factors; therefore, it is proposed that epigenetic mechanisms, particularly DNA methylation, can have a fundamental role in gene–environment interactions that are related with PD. Epigenetic changes in PD-associated genes are now widely studied in different populations, to discover the mechanisms that contribute to disease development and identify novel biomarkers for early diagnosis and future pharmacological treatment. While initial studies sought to find associations between promoter DNA methylation and the regulation of associated genes in PD brain tissue, more recent studies have described concordant DNA methylation patterns between blood and brain tissue DNA. These data justify the use of peripheral blood samples instead of brain tissue for epigenetic studies. Here, we summarize the current data about DNA methylation changes in PD and discuss the potential of DNA methylation as a potential biomarker for PD. Additionally, we discuss environmental and nutritional factors that have been implicated in DNA methylation. Although the search for significant DNA methylation changes and gene expression analyses of PD-associated genes have yielded inconsistent and contradictory results, epigenetic modifications remain under investigation for their potential to reveal the link between environmental risk factors and the development of PD.

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“…The precise cause of Parkinson's disease (PD) remains unknown; however, recent literature points to mitochondrial dysfunction, chronic inflammation and oxidative stress as the pivotal mechanisms of PD neuropathology [4]. Additionally, environmental risk factors such as carbon disulfide, cyanide, herbicides, methanol/organic solvents, pesticides and manganese have been implicated in PD-associated DAergic neuronal cell death [3,5].…”

Section: Introductionmentioning

confidence: 99%

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK) Enhances Activation of STAT3/NLRC4 Inflammasome Signaling Axis through PKCδ in Astrocytes: Implications for Parkinson’s Disease

Samidurai

Tarale

Janarthanam

et al. 2020

Cells

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Astrocytic dysfunction has been implicated in Parkinson’s disease (PD) pathogenesis. While the Tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/Fn14 signaling axis is known to play a role in PD-like neuropathology, the molecular mechanisms that govern this process remain poorly understood. Herein, we show that TWEAK levels are elevated in PD serum compared to controls. Moreover, using both U373 human astrocyte cells and primary mouse astrocytes, we demonstrate that TWEAK induces mitochondrial oxidative stress as well as protein kinase C delta (PKCδ) and signal transducer and activator of transcription 3 (STAT3) activation, accompanied by NLRC4 inflammasome activation and upregulation and release of proinflammatory cytokines, including IL-1β, TNF-α, and IL-18. Mechanistically, TWEAK-induced PKCδ activation enhances the STAT3/NLRC4 signaling pathway and other proinflammatory mediators through a mitochondrial oxidative stress-dependent mechanism. We further show that PKCδ knockdown and mito-apocynin, a mitochondrial antioxidant, suppress TWEAK-induced proinflammatory NLRC4/STAT3 signaling and cellular oxidative stress response. Notably, we validated our in vitro findings in an MPTP mouse model of PD and in mice receiving intrastriatal administration of TWEAK. These results indicate that TWEAK is a key regulator of astroglial reactivity and illustrate a novel mechanism by which mitochondrial oxidative stress may influence dopaminergic neuronal survival in PD.

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Global DNA methylation profiling of manganese-exposed human neuroblastoma SH-SY5Y cells reveals epigenetic alterations in Parkinson’s disease-associated genes

Cited by 45 publications

References 57 publications

Early postnatal manganese exposure causes arousal dysregulation and lasting hypofunctioning of the prefrontal cortex catecholaminergic systems

Early postnatal manganese exposure causes arousal dysregulation and lasting hypofunctioning of the prefrontal cortex catecholaminergic systems

Implications of DNA Methylation in Parkinson’s Disease

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK) Enhances Activation of STAT3/NLRC4 Inflammasome Signaling Axis through PKCδ in Astrocytes: Implications for Parkinson’s Disease

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