Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration.
Hui-Ming Gao,Paul T. Kotzbauer,Kunihiro Uryu,Susan Leight,John Q. Trojanowski,Virginia M.-Y. Lee +5 more
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TLDR
Understanding of the role of neuroinflammation and abnormal SYN in the pathogenesis of PD is advanced and new avenues for the discovery of more effective therapies for PD are opened.Abstract:
α-Synuclein (SYN) is the major component of Lewy bodies, the neuropathological hallmarks of Parkinson's disease (PD). Missense mutations and multiplications of the SYN gene cause autosomal dominant inherited PD. Thus, SYN is implicated in the pathogenesis of PD. However, the mechanism whereby SYN promotes neurodegeneration remains unclear. Familial PD with SYN gene mutations are rare because the majority of PD is sporadic and emerging evidence indicates that sporadic PD may result from genetic and environmental risk factors including neuroinflammation. Hence, we examined the relationship between SYN dysfunction and neuroinflammation in mediating dopaminergic neurodegeneration in mice and dopaminergic neuronal cultures derived from wild-type SYN and mutant A53T SYN transgenic mice in a murine SYN-null (SYNKO) background (M7KO and M83KO, respectively). Stereotaxic injection of an inflammagen, lipopolysaccharide, into substantia nigra of these SYN genetically engineered mice induced similar inflammatory reactions. In M7KO and M83KO, but not in SYNKO mice, the neuroinflammation was associated with dopaminergic neuronal death and the accumulation of insoluble aggregated SYN as cytoplasmic inclusions in nigral neurons. Nitrated/oxidized SYN was detected in these inclusions and abatement of microglia-derived nitric oxide and superoxide provided significant neuroprotection in neuron–glia cultures from M7KO mice. These data suggest that nitric oxide and superoxide released by activated microglia may be mediators that link inflammation and abnormal SYN in mechanisms of PD neurodegeneration. This study advances understanding of the role of neuroinflammation and abnormal SYN in the pathogenesis of PD and opens new avenues for the discovery of more effective therapies for PD.read more
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Mechanisms underlying inflammation in neurodegeneration.
TL;DR: There is evidence for a remarkable convergence in the mechanisms responsible for the sensing, transduction, and amplification of inflammatory processes that result in the production of neurotoxic mediators in neurodegenerative diseases.
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Neuroinflammation in Parkinson's disease: a target for neuroprotection?
TL;DR: Overall, available data support the importance of non-cell-autonomous pathological mechanisms in Parkinson's disease, which are mostly mediated by activated glial and peripheral immune cells.
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Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases
Yu Tang,Weidong Le +1 more
TL;DR: The changes of microglial phenotypes depend on the disease stages and severity; mastering the stage-specific switching of M1/M2 phenotypes within appropriate time windows may provide better therapeutic benefit.
Journal ArticleDOI
Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention.
TL;DR: The strongest direct evidence that chronic neuroinflammation may have a more important role to play in PD versus other neurodegenerative diseases is reviewed and genetic deficiency is not the only way to reduce protective factors in the brain which may function to keep microglial responses in check or regulate the sensitivity of DA neurons are proposed.
Journal ArticleDOI
Role of Oxidative Stress in Parkinson's Disease
TL;DR: NAD(P)H:quinone reductase (NQO1) and other antioxidant enzymes, whose gene expression are commonly under the regulation of the transcription factor Nrf2, can serve as target proteins utilized toward development of disease-modifying therapy for PD.
References
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Journal ArticleDOI
Mutation in the α-synuclein gene identified in families with Parkinson's disease
Mihael H. Polymeropoulos,Christian Lavedan,Elisabeth Leroy,Susan E. Ide,Anindya Dehejia,Amalia Dutra,Brian L. Pike,Holly Root,Jeffrey Rubenstein,Rebecca Boyer,Edward S. Stenroos,Settara C. Chandrasekharappa,Aglaia Athanassiadou,Theodore Papapetropoulos,William G. Johnson,Alice Lazzarini,Roger C. Duvoisin,Giuseppe Di Iorio,Lawrence I. Golbe,Robert L. Nussbaum +19 more
TL;DR: A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype.
Journal ArticleDOI
Alpha-synuclein in Lewy bodies.
Maria Grazia Spillantini,Marie L. Schmidt,Virginia M.-Y. Lee,John Q. Trojanowski,Ross Jakes,Michel Goedert +5 more
TL;DR: Strong staining of Lewy bodies from idiopathic Parkinson's disease with antibodies for α-synuclein, a presynaptic protein of unknown function which is mutated in some familial cases of the disease, indicates that the LewY bodies from these two diseases may have identical compositions.
Journal ArticleDOI
α-Synuclein Locus Triplication Causes Parkinson's Disease
Andrew B. Singleton,Matthew J. Farrer,Joshua C. Johnson,Amanda Singleton,Stephen Hague,Jennifer M. Kachergus,Mary M. Hulihan,Terhi Peuralinna,Amalia Dutra,Robert L. Nussbaum,Sarah Lincoln,Anthony Crawley,Melissa Hanson,Demetrius M. Maraganore,Charles H. Adler,Mark R. Cookson,Manfred D. Muenter,Melisa J. Baptista,David Miller,J. Blancato,John Hardy,Katrina Gwinn-Hardy +21 more
TL;DR: In this article, the α-synuclein was identified as the major component of Lewy bodies, the pathological hallmark of Parkinson's disease, and of glial cell cytoplasmic inclusions.
Journal ArticleDOI
Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease.
Rejko Krüger,Wilfried Kuhn,Thomas Müller,Dirk Woitalla,Manuel B. Graeber,Sigfried Kösel,Horst Przuntek,Jörg T. Epplen,Ludger Schöls,Olaf Riess +9 more
Journal ArticleDOI
The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia.
Juan J. Zarranz,Javier Alegre,Juan Carlos Gómez-Esteban,Elena Lezcano,Raquel Ros,Israel Ampuero,Lídice Vidal,Janet Hoenicka,Olga Rodriguez,Begoña Atarés,Verónica Llorens,Estrella Gomez Tortosa,Teodoro del Ser,David G. Munoz,Justo García de Yébenes +14 more
TL;DR: Dementia with Lewy bodies is related to mutation of α‐synuclein, and the novel mutation, that substitutes a dicarboxylic amino acid, glutamic acid, with a basic amino acid in a much conserved area of the protein, is likely to produce severe disturbance of protein function.
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