Reactive microgliosis: extracellular μ-calpain and microglia-mediated dopaminergic neurotoxicity

Levesque, Shannon; Wilson, Belinda; Gregoria, Vincent; Thorpe, Laura B.; Dallas, Shannon; Polikov, Vadim S.; Hong, Jau–Shyong; Block, Michelle L.

doi:10.1093/brain/awp333

Cited by 96 publications

(73 citation statements)

References 52 publications

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“…Our results show that, under certain conditions such as ␣-syn overexpression, calpain-1 can be released to the extracellular environment. It has been observed that 1-methyl-4-phenylpyridiniumtreated dopaminergic cells can release soluble factors such as calpain that activate microglia and are selectively toxic to other neurons (Levesque et al, 2010). Calpains are also externalized during certain inflammatory processes and play a role in the microenvironment of inflammatory cells (Ménard and el-Amine, 1996).…”

Section: Discussionmentioning

confidence: 99%

Reducing C-Terminal-Truncated Alpha-Synuclein by Immunotherapy Attenuates Neurodegeneration and Propagation in Parkinson's Disease-Like Models

Games

Valera²,

Spencer³

et al. 2014

Journal of Neuroscience

278

273

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Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are common neurodegenerative disorders of the aging population, characterized by progressive and abnormal accumulation of ␣-synuclein (␣-syn). Recent studies have shown that C-terminus (CT) truncation and propagation of ␣-syn play a role in the pathogenesis of PD/DLB. Therefore, we explored the effect of passive immunization against the CT of ␣-syn in the mThy1-␣-syn transgenic (tg) mouse model, which resembles the striato-nigral and motor deficits of PD. Mice were immunized with the new monoclonal antibodies 1H7, 5C1, or 5D12, all directed against the CT of ␣-syn. CT ␣-syn antibodies attenuated synaptic and axonal pathology, reduced the accumulation of CT-truncated ␣-syn (CT-␣-syn) in axons, rescued the loss of tyrosine hydroxylase fibers in striatum, and improved motor and memory deficits. Among them, 1H7 and 5C1 were most effective at decreasing levels of CT-␣-syn and higher-molecular-weight aggregates. Furthermore, in vitro studies showed that preincubation of recombinant ␣-syn with 1H7 and 5C1 prevented CT cleavage of ␣-syn. In a cell-based system, CT antibodies reduced cell-to-cell propagation of full-length ␣-syn, but not of the CT-␣-syn that lacked the 118 -126 aa recognition site needed for antibody binding. Furthermore, the results obtained after lentiviral expression of ␣-syn suggest that antibodies might be blocking the extracellular truncation of ␣-syn by calpain-1. Together, these results demonstrate that antibodies against the CT of ␣-syn reduce levels of CT-truncated fragments of the protein and its propagation, thus ameliorating PD-like pathology and improving behavioral and motor functions in a mouse model of this disease.

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Section: Discussionmentioning

confidence: 99%

Reducing C-Terminal-Truncated Alpha-Synuclein by Immunotherapy Attenuates Neurodegeneration and Propagation in Parkinson's Disease-Like Models

Games

Valera²,

Spencer³

et al. 2014

Journal of Neuroscience

278

273

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“…Mitochondrial impairment, due to genetic factors and/or environmental exposure to toxins could be the primary event triggering the pathological process. In this case, it is possible to hypothesize that microglia may become chronically activated in response to primary mitochondrial impairment and/or dopaminergic neuronal death, fueling a vicious cycle of microglial activation followed by further neuronal damage [84]. Indeed, there is evidence supporting the hypothesis that activated glial cells are able to damage dopaminergic neurons [85,86].…”

Section: Mitochondrial Impairment Neuroinflammation and Neurodegenementioning

confidence: 99%

Mitochondria and the Link Between Neuroinflammation and Neurodegeneration

Filippo

Chiasserini

Tozzi

et al. 2010

JAD

128

100

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Abstract. The innate immune response is thought to exert a dichotomous role in the brain. Indeed, although molecules of the innate immune response can promote repair mechanisms, during neuroinflammatory processes many harmful mediators are also released. Signs of neuroinflammation and neurodegeneration represent a ubiquitous pathological finding during the course of several different neurological diseases. Interestingly, it has been proposed that mitochondria may exert a crucial role in the pathogenesis of both inflammatory and neurodegenerative central nervous system disorders. In this review, we describe the mechanisms by which neuroinflammation and mitochondrial impairment may synergistically trigger a vicious cycle ultimately leading to neuronal death. In particular, we describe the close relationship existing among neuroinflammation, neurodegeneration, and mitochondrial impairment in three different widely-diffused neurological diseases in which these pathogenetic events coexist, namely multiple sclerosis, Parkinson's disease, and Alzheimer's disease.

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“…NOX2 is strongly upregulated in different CNS disorders where it generates large amounts of ROS. NOX2 activation is thought to regulate microglia activation, a hallmark of inflammatory gliosis observed in neuroinflammatory degenerative disorders [17,85]. As a major source of ROS, NOX2 can induce direct neuronal damage [128] and maintain microglial cells in an activated stage where they produce neurotoxic molecules like peroxynitrite and other inflammatory molecules [94].…”

mentioning

confidence: 99%

Targeting NOX enzymes in the central nervous system: therapeutic opportunities

Sorce

Krause

Jaquet

2012

Cell. Mol. Life Sci.

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Among the pathogenic mechanisms underlying central nervous system (CNS) diseases, oxidative stress is almost invariably described. For this reason, numerous attempts have been made to decrease reactive oxygen species (ROS) with the administration of antioxidants as potential therapies for CNS disorders. However, such treatments have always failed in clinical trials. Targeting specific sources of reactive oxygen species in the CNS (e.g. NOX enzymes) represents an alternative promising option. Indeed, NOX enzymes are major generators of ROS, which regulate progression of CNS disorders as diverse as amyotrophic lateral sclerosis, schizophrenia, Alzheimer disease, Parkinson disease, and stroke. On the other hand, in autoimmune demyelinating diseases, ROS generated by NOX enzymes are protective, presumably by dampening the specific immune response. In this review, we discuss the possibility of developing therapeutics targeting NADPH oxidase (NOX) enzymes for the treatment of different CNS pathologies. Specific compounds able to modulate the activation of NOX enzymes, and the consequent production of ROS, could fill the need for disease-modifying drugs for many incurable CNS pathologies.

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Reactive microgliosis: extracellular μ-calpain and microglia-mediated dopaminergic neurotoxicity

Cited by 96 publications

References 52 publications

Reducing C-Terminal-Truncated Alpha-Synuclein by Immunotherapy Attenuates Neurodegeneration and Propagation in Parkinson's Disease-Like Models

Reducing C-Terminal-Truncated Alpha-Synuclein by Immunotherapy Attenuates Neurodegeneration and Propagation in Parkinson's Disease-Like Models

Mitochondria and the Link Between Neuroinflammation and Neurodegeneration

Targeting NOX enzymes in the central nervous system: therapeutic opportunities

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