Zhang, W, Wang, T, Pei, Z, Miller, DS, Wu, X, Block, ML et al.. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson's disease. FASEB J 19: 533-542

Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina, USA.
The FASEB Journal (Impact Factor: 5.04). 04/2005; 19(6):533-542. DOI: 10.1096/fj.04-2751com


A growing body of evidence indicates that an inflammatory process in the substantia nigra, characterized by activation of resident microglia, likely either initiates or aggravates nigral neurodegeneration in Parkinson's disease (PD). To study the mechanisms by which nigral microglia are activated in PD, the potential role of -synuclein (a major component of Lewy bodies that can cause neurodegeneration when aggregated) in microglial activation was investigated. The results demonstrated that in a primary mesence- phalic neuron-glia culture system, extracellular aggre- gated human -synuclein indeed activated microglia; microglial activation enhanced dopaminergic neurode- generation induced by aggregated -synuclein. Further- more, microglial enhancement of -synuclein-mediated neurotoxicity depended on phagocytosis of -synuclein and activation of NADPH oxidase with production of reactive oxygen species. These results suggest that nigral neuronal damage, regardless of etiology, may release aggregated -synuclein into substantia nigra, which activates microglia with production of proinflam- matory mediators, thereby leading to persistent and progressive nigral neurodegeneration in PD. Finally, NADPH oxidase could be an ideal target for potential pharmaceutical intervention, given that it plays a critical role in -synuclein-mediated microglial activation and associated neurotoxicity.—Zhang, W., Wang, T., Pei, Z., Miller, D. S., Wu, X., Block, M. L., Wilson, B., Zhang, W., Zhou, Y., Hong, J. S., Zhang, J. Aggregated -synuclein activates microglia: a process leading to disease progression in Parkinson's disease. FASEB J. 19, 533-542 (2005)

Download full-text


Available from: Zhong Pei, Jan 05, 2015
  • Source
    • "The presence of reactive microglia was already detected in the substantia nigra of patients with neurodegenerative diseases, including PD, almost three decades ago [54], and later the involvement of microglia in neurodegenerative processes such as those of PD [55] was also shown. Others indicated that an inflammatory process in the substantia nigra, characterized by activation of microglia, probably initiates or aggravates nigral degeneration in PD [56]. Furthermore , chronic inflammation mediated by microglial cells is considered to be a fundamental process contributing to death of dopaminergic neurons in the brain, and the production of inflammatory agents by those cells characterizes the slow neurodegeneration seen in PD [57]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson’s disease is a neurodegenerative disorder where the main hallmark is the dopaminergic neuronal loss. Besides motor symptoms, PD also causes cognitive decline. Although current therapies focus on the restoration of dopamine levels in the striatum, prevention or disease-modifying therapies are urgently needed. Valproic acid (VA) is a wide spectrum antiepileptic drug, exerting many biochemical and physiological effects. It has been shown to inhibit histone deacetylase which seems to be associated with the drug neuroprotective action. The objectives were to study the neuroprotective properties of VA in a model of Parkinson’s disease, consisting in the unilateral striatal injection of the neurotoxin 6-OHDA. For that, male Wistar rats (250 g) were divided into the groups: sham-operated (SO), untreated 6-OHDA-lesioned, and 6-OHDA-lesioned treated with VA (25 or 50 mg/kg). Oral treatments started 24 h after the stereotaxic surgery and continued daily for 2 weeks, when the animals were subjected to behavioral evaluations (apomorphine-induced rotations and open-field tests). Then, they were sacrificed and had their mesencephalon, striatum, and hippocampus dissected for neurochemical (DA and DOPAC determinations), histological (Fluoro-Jade staining), and immunohistochemistry evaluations (TH, OX-42, GFAP, TNF-alpha, and HDAC). The results showed that VA partly reversed behavioral and neurochemical alterations observed in the untreated 6-OHDA-lesioned rats. Besides, VA also decreased neuron degeneration in the striatum and reversed the TH depletion observed in the mesencephalon of the untreated 6-OHDA groups. This neurotoxin increased the OX-42 and GFAP immunoreactivities in the mesencephalon, indicating increased microglia and astrocyte reactivities, respectively, which were reversed by VA. In addition, the immunostainings for TNF-alpha and HDAC demonstrated in the untreated 6-OHDA-lesioned rats were also decreased after VA treatments. These results were observed not only in the CA1 and CA3 subfields of the hippocampus, but also in the temporal cortex. In conclusion, we showed that VA partly reversed the behavioral, neurochemical, histological, and immunohistochemical alterations observed in the untreated 6-OHDA-lesioned animals. These effects are probably related to the drug anti-inflammatory activity and strongly suggest that VA is a potential candidate to be included in translational studies for the treatment of neurodegenerative diseases as PD.
    Journal of Neurodegenerative Diseases 08/2015; 2015:1-14. DOI:10.1155/2015/313702
  • Source
    • "PD has also a well-recognized inflammatory component. Release of a-synuclein extracellularly may activate microglial cells and lead to an inflammatory reaction (Zhang et al., 2005; Reynolds et al., 2008). CD4þ T regulatory cells were also found to mediate microglial activation by nitrated a-synuclein (Benner et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The endoplasmic reticulum (ER) is a critical organelle for normal cell function and homeostasis. Disturbance in the protein folding process in the ER, termed ER stress, leads to the activation of unfolded protein response (UPR) that encompasses a complex network of intracellular signaling pathways. The UPR can either restore ER homeostasis or activate pro-apoptotic pathways depending on the type of insults, intensity and duration of the stress, and cell types. ER stress and the UPR have recently been linked to inflammation in a variety of human pathologies including autoimmune, infectious, neurodegenerative, and metabolic disorders. In the cell, ER stress and inflammatory signaling share extensive regulators and effectors in a broad spectrum of biological processes. In spite of different etiologies, the two signaling pathways have been shown to form a vicious cycle in exacerbating cellular dysfunction and causing apoptosis in many cells and tissues. However, the interaction between ER stress and inflammation in many of these diseases remains poorly understood. Further understanding of the biochemistry, cell biology, and physiology may enable the development of novel therapies that spontaneously target these pathogenic pathways. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Cellular Physiology 07/2015; 22(10). DOI:10.1002/jcp.25098 · 3.84 Impact Factor
  • Source
    • "Importantly, this mechanism is unique to microglia, with astrocytic uptake of AS shown to be TLR4-independent. In contrast, the role for TLR4 in Parkinson's disease is confounded by evidence showing that genetic TLR4 deletion results in reduced phagocytic activity of microglia, leading to heightened AS accumulation and exacerbated neurodegeneration [65] [66]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Regimen-related toxicities remain a priority concern within the field of supportive care in cancer. Despite this, many forms of toxicity are under reported and consequently poorly characterised. Although there have been significant improvements in our understanding of regimen-related toxicities, symptom management continues to occur independently raising concerns such as drug interactions and the tendency to emphasise management of a single symptom at the expense of others. This review focuses on two important toxicities induced by chemotherapy; neuropathy/pain and gastrointestinal toxicity, introducing the Toll-like receptor (TLR) 4 pathway as a common component of their pathobiology. Given the global observation of toxicity clusters, identification of a common initiating factor provides an excellent opportunity to simultaneously target multiple side effects of anticancer treatment. Furthermore, identification of common biological underpinnings could perhaps reduce polypharmacy and have pharmacoeconomic benefits. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Cancer Treatment Reviews 12/2014; 41(2). DOI:10.1016/j.ctrv.2014.11.005 · 7.59 Impact Factor
Show more