p38 MAPK-DRP1 signaling is involved in mitochondrial dysfunction and cell death in mutant A53T α-synuclein model of Parkinson's disease

Chen, Gui; Ren, Yixian; Chen, Jialong; Wu, Xian; Mao, Kanmin; Li, Huihui; Yu, Honglin; Zou, Fei; Li, Wenjun

doi:10.1016/j.taap.2019.114874

Cited by 65 publications

(49 citation statements)

References 30 publications

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“…With these limitations in mind, we were able to successfully identify 3 compounds with robust modulation of induced aggregation, clustering on p38 MAPK and PKC, which is supported by previous studies having suggested these pathways as potential therapeutic targets (Gui et al, 2020;Iba et al, 2020;Iwata et al, 2001;Obergasteiger et al, 2018) , (Do Van et al, 2016;Weinreb et al, 2005;Youdim et al, 2003). While evidence for a protective role of modulation of these pathways has been suggested, the mechanism by which they might cause the protection is currently not known.…”

Section: Utilizing Fret Hts For Compound Discoverysupporting

confidence: 60%

FRET-based screening in HEK293T identifies p38 MAPK and PKC inhibition as therapeutic targets for α-synuclein aggregation

Svanbergsson

Martinsson

et al. 2021

Preprint

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Aggregation of α-synuclein is associated with neurodegeneration and a hallmark pathology in synucleinopathies. These aggregates are thought to function as prion-like particles where the conformation of misfolded α-synuclein determines the induced pathologys traits similar to prion diseases. Still, little is known about the molecular targets facilitating the conformation-specific biological effects, but their identification could form the basis for new therapeutic intervention. High-throughput screening (HTS) of annotated compound libraries could facilitate mechanistic investigation by identifying targets with impact on α-synuclein aggregation. To this end, we developed a FRET-based cellular reporter in HEK293T cells, with sensitivity down to 6.5 nM α-synuclein seeds. Using this model system, we identified GF109203X, SB202190, and SB203580 as inhibitors capable of preventing induction of α-synuclein aggregation via inhibition of p38 MAPK and PKC, respectively. Our findings highlight the value HTS brings to the mechanistic investigation of α-synuclein aggregation while simultaneously identifying novel therapeutic compounds.

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Section: Utilizing Fret Hts For Compound Discoverysupporting

confidence: 60%

FRET-based screening in HEK293T identifies p38 MAPK and PKC inhibition as therapeutic targets for α-synuclein aggregation

Svanbergsson

Martinsson

et al. 2021

Preprint

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“…The p38 mitogen-activated protein kinase (MAPK) activation is related to redox signaling transduction via stimulation of stress responses, including mitochondrial dysfunction [ 27 , 28 , 29 , 30 , 31 ]. Therefore, the protective antioxidant effect of chrysoeriol on the p38 MAPK pathway was determined in ARPE-19 cells.…”

Section: Resultsmentioning

confidence: 99%

Antioxidative Effects of Chrysoeriol via Activation of the Nrf2 Signaling Pathway and Modulation of Mitochondrial Function

et al. 2021

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Retinal pigment epithelium (RPE) cell dysfunction caused by excessive oxidative damage is partly involved in age-related macular degeneration, which is among the leading causes of visual impairment in elderly people. Here, we investigated the protective role of chrysoeriol against hydrogen peroxide (H2O2)-induced oxidative stress in RPE cells. The cellular viability, reactive oxygen species (ROS) generation, and mitochondrial function of retinal ARPE-19 cells were monitored under oxidative stress or pre-treatment with chrysoeriol. The expression levels of mitochondrial-related genes and associated transcription factors were assessed using reverse transcription–quantitative polymerase chain reaction (RT-qPCR). Moreover, the protein expression of antioxidant signal molecules was characterized by Western blot analysis. Chrysoeriol significantly increased cell viability, reduced ROS generation, and increased the occurrence of antioxidant molecules in H2O2-treated ARPE-19 cells. Additionally, mitochondrial dysfunction caused by H2O2-induced oxidative stress was also considerably diminished by chrysoeriol treatment, which reduced the mitochondrial membrane potential (MMP) and upregulated mitochondrial-associated genes and proteins. Chrysoeriol also markedly enhanced key transcription factors (Nrf2) and antioxidant-associated genes (particularly HO-1 and NQO-1). Therefore, our study confirms the protective effect of chrysoeriol against H2O2-induced oxidative stress in RPE cells, thus confirming that it may prevent mitochondrial dysfunction by upregulating antioxidant-related molecules.

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“…Moreover, the identification of roles independent of infections led to the extension of what has been called "sterile inflammation" (e.g., injury, illness, or aging). In particular, the activity of p38α has been associated with (a) the progression of the expression of protein markers of the aging phenotype [20][21][22]; (b) the development of inflammation and oxidative stress [10,23] associated with neurodegeneration, including Alzheimer's [24][25][26], lipopolysaccharide (LPS) [27,28], and Parkinson's [29,30] diseases; cardiovascular [31] and musculoskeletal diseases; diabetes [32]; rheumatoid arthritis [33]; and toxin-induced preterm birth [34]. Importantly, small molecule inhibitors of the p38 MAPK family have been developed, and show efficacy in blocking the production of proinflammatory cytokines, such as interleukin (IL)-1β and tumor necrosis factor alpha (TNF-α) [35].…”

Section: P38 Mitogen-activated Protein Kinases (P38-mapk)mentioning

confidence: 99%

Involvement of p38 MAPK in Synaptic Function and Dysfunction

Falcicchia

Tozzi

Arancio

et al. 2020

IJMS

137

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Many studies have revealed a central role of p38 MAPK in neuronal plasticity and the regulation of long-term changes in synaptic efficacy, such as long-term potentiation (LTP) and long-term depression (LTD). However, p38 MAPK is classically known as a responsive element to stress stimuli, including neuroinflammation. Specific to the pathophysiology of Alzheimer’s disease (AD), several studies have shown that the p38 MAPK cascade is activated either in response to the Aβ peptide or in the presence of tauopathies. Here, we describe the role of p38 MAPK in the regulation of synaptic plasticity and its implication in an animal model of neurodegeneration. In particular, recent evidence suggests the p38 MAPK α isoform as a potential neurotherapeutic target, and specific inhibitors have been developed and have proven to be effective in ameliorating synaptic and memory deficits in AD mouse models.

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p38 MAPK-DRP1 signaling is involved in mitochondrial dysfunction and cell death in mutant A53T α-synuclein model of Parkinson's disease

Cited by 65 publications

References 30 publications

FRET-based screening in HEK293T identifies p38 MAPK and PKC inhibition as therapeutic targets for α-synuclein aggregation

FRET-based screening in HEK293T identifies p38 MAPK and PKC inhibition as therapeutic targets for α-synuclein aggregation

Antioxidative Effects of Chrysoeriol via Activation of the Nrf2 Signaling Pathway and Modulation of Mitochondrial Function

Involvement of p38 MAPK in Synaptic Function and Dysfunction

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