Integrin CD11b mediates α-synuclein-induced activation of NADPH oxidase through a Rho-dependent pathway

Hou, Liyan; Bao, Xiaoyong; Zang, Caixia; Yang, Hanyu; Sun, Fuqiang; Che, Yuning; Wu, Xing; Li, Shao; Zhang, Dan; Wang, Qingshan

doi:10.1016/j.redox.2017.11.010

Cited by 80 publications

(64 citation statements)

References 45 publications

(60 reference statements)

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“…This also indicated that a PI3K-dependent mechanism controlled NOX activation in the present setting. Still consistent with our results, Hou et al (2018) reported that p47phox was robustly activated by αSa in microglial cultures. As expected this effect was totally reversed by PI3K inhibition, which is coherent with a previous report showing that PI3K controls NOX2 activation in microglial cells exposed to αS oligomers .…”

Section: αSa-mediated Glutamate Release In Microglial Cells Resultssupporting

confidence: 93%

Microglial glutamate release evoked by α‐synuclein aggregates is prevented by dopamine

Pereira

Acuña

Hamadat

et al. 2018

Glia

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When activated, microglial cells have the potential not only to secrete typical proinflammatory mediators but also to release the neurotransmitter glutamate in amounts that may promote excitotoxicity. Here, we wished to determine the potential of the Parkinson's disease (PD) protein α‐Synuclein (αS) to stimulate glutamate release using cultures of purified microglial cells. We established that glutamate release was robustly increased when microglial cultures were treated with fibrillary aggregates of αS but not with the native monomeric protein. Promotion of microglial glutamate release by αS aggregates (αSa) required concomitant engagement of TLR2 and P2X7 receptors. Downstream to cell surface receptors, the release process was mediated by activation of a signaling cascade sequentially involving phosphoinositide 3‐kinase (PI3K) and NADPH oxidase, a superoxide‐producing enzyme. Inhibition of the Xc‐ antiporter, a plasma membrane exchange system that imports extracellular l‐cystine and exports intracellular glutamate, prevented the release of glutamate induced by αSa, indicating that system Xc‐ was the final effector element in the release process downstream to NADPH oxidase activation. Of interest, the stimulation of glutamate release by αSa was abrogated by dopamine through an antioxidant effect requiring D1 dopamine receptor activation and PI3K inhibition. Altogether, present data suggest that the activation of microglial cells by αSa may possibly result in a toxic build‐up of extracellular glutamate contributing to excitotoxic stress in PD. The deficit in dopamine that characterizes this disorder may further aggravate this process in a vicious circle mechanism.

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Section: αSa-mediated Glutamate Release In Microglial Cells Resultssupporting

confidence: 93%

Microglial glutamate release evoked by α‐synuclein aggregates is prevented by dopamine

Pereira

Acuña

Hamadat

et al. 2018

Glia

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“…α-syn 29–40, a α-syn specific peptide, has been described to activate superoxide generation in microglia, which causes DA neuronal damage [ 87 ]. Later, it was described that extracellular α-syn binds to CD11b integrin in microglia and controls NOX2 activation via a RhoA-dependent pathway [ 88 ].…”

Section: Small Gtpases Of the Rho Familymentioning

confidence: 99%

Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases

Sastre

Montoro

Gálvez‐Martín

et al. 2020

IJMS

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Small guanosine triphosphatases (GTPases) of the Ras superfamily are key regulators of many key cellular events such as proliferation, differentiation, cell cycle regulation, migration, or apoptosis. To control these biological responses, GTPases activity is regulated by guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in some small GTPases also guanine nucleotide dissociation inhibitors (GDIs). Moreover, small GTPases transduce signals by their downstream effector molecules. Many studies demonstrate that small GTPases of the Ras family are involved in neurodegeneration processes. Here, in this review, we focus on the signaling pathways controlled by these small protein superfamilies that culminate in neurodegenerative pathologies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Specifically, we concentrate on the two most studied families of the Ras superfamily: the Ras and Rho families. We summarize the latest findings of small GTPases of the Ras and Rho families in neurodegeneration in order to highlight these small proteins as potential therapeutic targets capable of slowing down different neurodegenerative diseases.

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“…Moreover, this microglia‐driven oxidative stress will lead to oxidation of a‐syn in nearby cells which will further feed the neuro‐toxic process (Shavali, Combs, & Ebadi, ). The a‐syn‐induced oxidative stress has been related to CD11b and resultant PHOX NADPH oxidase activation (Hou et al., ; Jin et al., ; Zhang et al., , ). Multiple labs have shown now that a‐syn can initiate a pro‐inflammatory response in microglia inducing production of IL‐6, IL‐1β, and TNF (Couch, Alvarez‐Erviti, Sibson, Wood, & Anthony, ; Klegeris et al., ; Lee et al., , ; Roodveldt et al., ; Su et al., ).…”

Section: The Role Of A‐synuclein In the Microglia Response In Parkinsmentioning

confidence: 99%

Immune system responses in Parkinson's disease: Early and dynamic

Tansey

Romero‐Ramos

2018

Eur J of Neuroscience

122

127

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The neuropathological hallmarks of Parkinson's disease (PD) are the degeneration and death of dopamine‐producing neurons in the ventral midbrain, the widespread intraneuronal aggregation of alpha‐synuclein (α) in Lewy bodies and neurites, neuroinflammation, and gliosis. Signs of microglia activation in the PD brain postmortem as well as during disease development revealed by neuroimaging, implicate immune responses in the pathophysiology of the disease. Intensive research during the last two decades has advanced our understanding of the role of these responses in the disease process, yet many questions remain unanswered. A transformative finding in the field has been the confirmation that in vivo microglia are able to respond directly to pathological a‐syn aggregates but also to neuronal dysfunction due to intraneuronal a‐syn toxicity well in advance of neuronal death. In addition, clinical research and disease models have revealed the involvement of both the innate and adaptive immune systems. Indeed, the data suggest that PD leads not only to a microglia response, but also to a cellular and humoral peripheral immune response. Together, these findings compel us to consider a more holistic view of the immunological processes associated with the disease. Central and peripheral immune responses aimed at maintaining neuronal health will ultimately have consequences on neuronal survival. We will review here the most significant findings that have contributed to the current understanding of the immune response in PD, which is proposed to occur early, involve peripheral and brain immune cells, evolve as neuronal dysfunction progresses, and is likely to influence disease progression.

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Integrin CD11b mediates α-synuclein-induced activation of NADPH oxidase through a Rho-dependent pathway

Cited by 80 publications

References 45 publications

Microglial glutamate release evoked by α‐synuclein aggregates is prevented by dopamine

Microglial glutamate release evoked by α‐synuclein aggregates is prevented by dopamine

Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases

Immune system responses in Parkinson's disease: Early and dynamic

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