Absence of Glia Maturation Factor Protects Dopaminergic Neurons and Improves Motor Behavior in Mouse Model of Parkinsonism

Khan, Mohammad Moshahid; Zaheer, Smita; Thangavel, Ramasamy; Patel, Meena; Kempuraj, Duraisamy; Zaheer, Asgar

doi:10.1007/s11064-015-1553-x

Cited by 17 publications

(23 citation statements)

References 48 publications

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“…GMF-induced neuroinflammation leads to the death of neurons in the CNS (Zaheer et al, 2007). GMF expression level is increased in the CNS of neurodegenerative diseases including EAE (Zaheer et al, 2011b; Thangavel et al, 2012), while GMF knockdown suppresses dopaminergic neuronal loss, glial activation and the expression levels of proinflammatory mediators in the substantia nigra of MPTP-treated animal model of PD (Khan et al, 2015). We have previously reported the expression of GMF in human and mouse mast cells, as GMF was also reported in several extra CNS cells in the body (Kempuraj et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson’s Disease

Kempuraj

Selvakumar

Zaheer

et al. 2017

J Neuroimmune Pharmacol

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Parkinson’s disease (PD) is a progressive movement disorder characterized by neuroinflammation and dopaminergic neurodegeneration in the brain. 1-methyl-4-phenylpyridinium (MPP+), a metabolite of the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces the release of inflammatory mediators from glial cells and neurons. Glia maturation factor (GMF), a brain proinflammatory protein, MPP+, and mast cell-derived inflammatory mediators induce neurodegeneration which eventually leads to PD. However, the precise mechanisms underlying interaction between glial cells, neurons and mast cells in PD still remain elusive. In the present study, mouse bone marrow-derived mast cells (BMMCs) and mouse fetal brain-derived mixed glia/neurons, astrocytes and neurons were incubated with MPP+, GMF and mast cell-derived inflammatory mediators mouse mast cell protease-6 (MMCP-6), MMCP-7 or tryptase/brain-specific serine protease-4 (tryptase/BSSP-4). Inflammatory mediators released from these cells in the culture medium were quantitated by enzyme-linked immunosorbent assay. Neurodegeneration was quantified by measuring total neurite outgrowth following microtubule-associated protein-2 immunocytochemistry. MPP+− induced significant neurodegeneration with reduced total neurite outgrowth. MPP+− induced the release of tryptase/BSSP-4 from the mouse mast cells, and tryptase/BSSP-4 induced chemokine (C-C motif) ligand 2 (CCL2) release from astrocytes and glia/neurons. Overall our results suggest that MPP+, GMF, MMCP-6 or MMCP-7 stimulate glia/neurons, astrocytes or neurons to release CCL2 and matrix metalloproteinase-3. Additionally, CD40L expression is increased in BMMCs after incubation with MPP+ in a co-culture system consisting of BMMCs and glia/neurons. We propose that mast cell interaction with glial cells and neurons during neuroinflammation can be explored as a new therapeutic target for PD.

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Section: Discussionmentioning

confidence: 99%

Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson’s Disease

Kempuraj

Selvakumar

Zaheer

et al. 2017

J Neuroimmune Pharmacol

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“…We recently showed that GMF-deficiency in astrocytes upregulates antioxidant level and reduces the production of ROS in MPP + -induced toxicity [8]. Our another study showed that absence of GMF suppresses dopaminergic neuronal loss, glial activation, and expression of inflammatory mediators in the SNpc and striatum of MPTP treated mice [15]. We also recently demonstrated MPP + -induced dopaminergic neuronal loss in primary cultures of the mouse mesencephalic neurons/glia obtained from GMF-KO and wild-type mice [54].…”

Section: Discussionmentioning

confidence: 99%

“…Glia maturation factor (GMF), a brain protein previously isolated, sequenced and cloned in our laboratory [9–12] has reported to activate glial cells and induce neuroinflammation and neurodegeneration in vivo and in vitro [13–15]. Overexpression of GMF increased Experimental Autoimmune Encephalomyelitis (EAE) disease severity and induced significant releasee of proinflammatory cytokines and chemokines from astrocytes [16,17].…”

Section: Introductionmentioning

confidence: 99%

Mast Cells Release Chemokine CCL2 in Response to Parkinsonian Toxin 1-Methyl-4-Phenyl-Pyridinium (MPP+)

et al. 2015

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Microglial activation and release of inflammatory cytokines and chemokines are crucial events in neuroinflammation. Microglial cells interact and respond to other inflammatory cells such as T cells and mast cells as well as inflammatory mediators secreted from these cells. Recent studies have shown that neuroinflammation causes and accelerates neurodegenerative disease such as Parkinson’s disease (PD) pathogenesis. 1-methyl-4-phenyl-pyridinium ion (MPP+), the active metabolite of neurotoxin 1- methyl -4- phenyl -1,2,3,6-tetrahydro pyridine (MPTP) activates glial cells and mediate neurodegeneration through release of inflammatory mediators. We have shown that glia maturation factor (GMF) activates glia and induces neuroinflammation and neurodegeneration and that MPP+ activates mast cells and release proinflammatory cytokines and chemokines. The chemokine (C-C motif) ligand 2 (CCL2) levels have been shown to be elevated and play a role in PD pathogenesis. In the present study, we analyzed if MPP+ activates mouse and human mast cells to release chemokine CCL2. Mouse bone marrow-derived mast cells (BMMCs) and human umbilical cord blood-derived cultured mast cells (hCBMCs) were incubated with MPP+ (10 μM) for 24 h and CCL2 levels were measured in the supernatant media by ELISA. MPP+-significantly-induced CCL2 release from BMMCs and hCBMCs. Additionally, GMF overexpression in BMMCs obtained from wild-type mice released significantly more CCL2, while BMMCs obtained from GMF-deficient mice showed less CCL2 release. Further, we show that MPP+-induced CCL2 release was greater in BMMCs-astrocyte co-culture conditions. Uncoupling protein 4 (UCP4) which is implicated in neurodegenerative diseases including PD was detected in BMMCs by immunocytochemistry. Our results suggest that mast cells may play role in PD pathogenesis.

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“…Upregulation of GMF expression causes inflammation in neurodegenerative disorders [6]. It was for the first time discovered, purified, sequenced and sub-cloned from bovine brain in our laboratory [7–12]. Previous reports from our laboratory showed that GMF is mainly co-localized and expressed in the vicinity of Aβ and tau in the temporal cortex of human AD brain [13, 14].…”

Section: Introductionmentioning

confidence: 99%

Co-Localization of Glia Maturation Factor with NLRP3 Inflammasome and Autophagosome Markers in Human Alzheimer’s Disease Brain

Ahmed

Iyer

Thangavel

et al. 2017

JAD

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the presence of intracellular neurofibrillary tangles (NFTs) containing hyper-phosphorylated tau, and the extracellular deposition of amyloid plaques (APs) with misfolded amyloid–β (Aβ) peptide. Glia maturation factor (GMF), a highly conserved pro-inflammatory protein, isolated and cloned in our laboratory has been shown to activate glial cells leading to neuroinflammation and neurodegeneration in AD. We hypothesized that inflammatory reactions promoted by NLRP3-Caspase-1inflammasome pathway trigger dysfunction in autophagy and accumulation of Aβ which is amplified and regulated by GMF in AD. In this study, using immunohistochemical techniques we analyzed components of the NLRP3 inflammasome and autophagy-lysosomal markers in relation to Aβ, p-tau and GMF in human post-mortem AD and age-matched non-AD brains. Tissue sections were prepared from the temporal cortex of human post-mortem brains. Here, we demonstrate an increased expression of the inflammasome components NLRP3 and Caspase-1 and the products of inflammasome activation IL-1β and IL-18 along with GMF in the temporal cortex of AD brains. These inflammasome components and the pro-inflammatory cytokines co-localized with GMF in the vicinity and periphery of the amyloid plaques and NFTs. Moreover, using double immunofluorescence staining, AD brain displayed an increase in the autophagy SQSTM1/p62 and LC3 positive vesicles and the lysosomal marker LAMP1 that also co-localized with GMF, amyloid beta and hyper-phosphorylated p-tau. Our results indicate that in AD, the neuroinflammation promoted by the NLRP3 inflammasome may be amplified and regulated by GMF, which further impairs clearance of protein aggregates mediated by the autophagosomal pathway.

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Absence of Glia Maturation Factor Protects Dopaminergic Neurons and Improves Motor Behavior in Mouse Model of Parkinsonism

Cited by 17 publications

References 48 publications

Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson’s Disease

Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson’s Disease

Mast Cells Release Chemokine CCL2 in Response to Parkinsonian Toxin 1-Methyl-4-Phenyl-Pyridinium (MPP+)

Co-Localization of Glia Maturation Factor with NLRP3 Inflammasome and Autophagosome Markers in Human Alzheimer’s Disease Brain

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