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Synuclein microglia

Kai-Chih Hung, Hui-Ju Huang, Yi-Ting Wang, Anya Maan-Yuh Lin
ETHNOPHARMACOLOGICAL RELEVANCE: Neuroinflammation, oxidative stress, and protein aggregation form a vicious cycle in the pathophysiology of Parkinson's disease (PD); activated microglia is the main location of neuroinflammation. A Chinese medicine book, "Shanghan Lun", known as the "Treatises on Cold damage Diseases" has suggested that Scutellaria baicalensis Georgi is effective in treating CNS diseases. The anti-inflammatory mechanisms of baicalein, a phenolic flavonoid in the dried root of Scutellaria baicalensis Georgi, remain to be explored...
October 11, 2016: Journal of Ethnopharmacology
Neal K Bennett, Rebecca Chmielowski, Dalia S Abdelhamid, Jonathan J Faig, Nicola Francis, Jean Baum, Zhiping P Pang, Kathryn E Uhrich, Prabhas V Moghe
Neuroinflammation, a common neuropathologic feature of neurodegenerative disorders including Parkinson disease (PD), is frequently exacerbated by microglial activation. The extracellular protein α-synuclein (ASYN), whose aggregation is characteristic of PD, remains a key therapeutic target, but the control of synuclein trafficking and aggregation within microglia has been challenging. First, we established that microglial internalization of monomeric ASYN was mediated by scavenger receptors (SR), CD36 and SRA1, and was rapidly accompanied by the formation of ASYN oligomers...
October 4, 2016: Biomaterials
Suraj S Pradhan, Kirstie Salinas, Alexis C Garduno, Jenny U Johansson, Qian Wang, Amy Manning-Bog, Katrin I Andreasson
Inflammation is a ubiquitous factor accompanying normal aging and neurodegeneration, and recent studies indicate a major contribution of inducible cyclooxygenase (COX-2) and its downstream prostaglandin signaling pathways in modulating neuroinflammatory responses and neuronal function. We have previously shown that the prostaglandin PGE2 receptor EP4 suppresses innate immune responses in models of systemic inflammation. Here we investigated the role of the EP4 receptor in models of Parkinson's disease (PD)...
October 12, 2016: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
X T Li, D F Cai
Parkinson's disease(PD)was the second most common neurodegenerative disorder after Alzheimer's disease. Incidence of PD was ascending year by year. The etiology of PD is poorly understood, involving aging, genetic and environmental factors. Recently, environmental compound had attracted more and more research interest. Studies and extrapolation from epidemiology, animal experiments and cell culture suggested that environmental compound had involved in the molecular mechanisms including mitochondrial dysfunction, oxidative stress, microglia activation, abnormal aggregation of α-synuclein and autophagy damage ,which seemed to increase PD risk...
October 6, 2016: Zhonghua Yu Fang Yi Xue za Zhi [Chinese Journal of Preventive Medicine]
Marija Iljina, Laura Tosatto, Minee L Choi, Jason C Sang, Yu Ye, Craig D Hughes, Clare E Bryant, Sonia Gandhi, David Klenerman
The protein alpha-synuclein (αS) self-assembles into toxic beta-sheet aggregates in Parkinson's disease, while it is proposed that αS forms soluble alpha-helical multimers in healthy neurons. Here, we have made αS multimers in vitro using arachidonic acid (ARA), one of the most abundant fatty acids in the brain, and characterized them by a combination of bulk experiments and single-molecule Fӧrster resonance energy transfer (sm-FRET) measurements. The data suggest that ARA-induced oligomers are alpha-helical, resistant to fibril formation, more prone to disaggregation, enzymatic digestion and degradation by the 26S proteasome, and lead to lower neuronal damage and reduced activation of microglia compared to the oligomers formed in the absence of ARA...
September 27, 2016: Scientific Reports
Alana Hoffmann, Benjamin Ettle, Ariane Bruno, Anna Kulinich, Anna-Carin Hoffmann, Julia von Wittgenstein, Jürgen Winkler, Wei Xiang, Johannes C M Schlachetzki
Synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are defined by the presence of intracellular alpha-synuclein aggregates in neurons and/or oligodendrocytes. In addition, post mortem tissue analysis revealed profound changes in microglial morphology, indicating microglial activation and neuroinflammation. Thus, alpha-synuclein may directly activate microglia, leading to increased production of key pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β), which in turn modulates the disease progression...
October 28, 2016: Biochemical and Biophysical Research Communications
Qimei Wu, Xiaoyu Yang, Yu Zhang, Lei Zhang, Linyin Feng
Daily stress is associated with increased risk for various diseases, and numerous studies have provided evidence that environmental stress leads to deleterious effects on the central nervous system. However, it remains unclear whether chronic stress exacerbates the progression of Parkinson's disease (PD). To investigate this hypothesis, we determined the effect of chronic mild stress (CMS) on the pathogenesis of PD in a transgenic mice line that overexpresses the human A53T mutant α-synuclein (A53T Tg mice)...
November 2016: Experimental Neurology
Claire Hoenen, Audrey Gustin, Cindy Birck, Mélanie Kirchmeyer, Nicolas Beaume, Paul Felten, Luc Grandbarbe, Paul Heuschling, Tony Heurtaux
Parkinson's disease (PD) is histologically described by the deposition of α-synuclein, whose accumulation in Lewy bodies causes dopaminergic neuronal death. Although most of PD cases are sporadic, point mutations of the gene encoding the α-synuclein protein cause inherited forms of PD. There are currently six known point mutations that result in familial PD. Oxidative stress and neuroinflammation have also been described as early events associated with dopaminergic neuronal degeneration in PD. Though it is known that microglia are activated by wild-type α-synuclein, little is known about its mutated forms and the signaling cascades responsible for this microglial activation...
2016: PloS One
Annika Scheffold, Inge R Holtman, Sandra Dieni, Nieske Brouwer, Sarah-Fee Katz, Billy Michael Chelliah Jebaraj, Philipp J Kahle, Bastian Hengerer, André Lechel, Stephan Stilgenbauer, Erik W G M Boddeke, Bart J L Eggen, Karl-Lenhard Rudolph, Knut Biber
Parkinson's disease is one of the most common neurodegenerative disorders of the elderly and ageing hence described to be a major risk factor. Telomere shortening as a result of the inability to fully replicate the ends of linear chromosomes is one of the hallmarks of ageing. The role of telomere dysfunction in neurological diseases and the ageing brain is not clarified and there is an ongoing discussion whether telomere shortening is linked to Parkinson's disease. Here we studied a mouse model of Parkinson's disease (Thy-1 [A30P] α-synuclein transgenic mouse model) in the background of telomere shortening (Terc knockout mouse model)...
August 22, 2016: Acta Neuropathologica Communications
Hyun Jung Park, Se Hee Oh, Ha Na Kim, Yu Ju Jung, Phil Hyu Lee
Microglia in the brain show distinctive phenotypes that serve different functions. In particular, M2-polarized microglia are anti-inflammatory and phagocytic cells that serve a restorative function. In this study, we investigated whether mesenchymal stem cells (MSCs) enhance the phagocytic clearance of α-synuclein via M2 microglia polarization, and thereby exert neuroprotective effects in α-synuclein-enriched experimental models and patients with multiple system atrophy (MSA). Treatment of BV2 cells with α-synuclein induced an inflammatory phenotype, whereas co-culture of α-synuclein-treated BV2 cells with MSCs induced an anti-inflammatory M2 phenotype, with decreased α-synuclein levels and increased lysosomal activity, leading to greater viability of neuronal cells co-cultured with BV2 cells...
August 6, 2016: Acta Neuropathologica
Dimitry A Chistiakov, Alexander A Chistiakov
Exosomes play a key role in delivery of various biological material and complex signals from one cell to another at long distances. These small extracellular vehicles are involved in mediating multiple physiological and pathogenic processes. In neurodegenerative diseases such as Parkinson's disease (PD), exosomes contribute to disease propagation through transferring misfolded proteins from affected cells to normal cells. In PD, progressive degeneration of neurons arises from the extensive accumulation of toxic forms of α-synuclein in the cytoplasm...
July 29, 2016: Acta Neurologica Belgica
Kyoko Suzuki, Akira Yamaguchi, Shoji Yamanaka, Seiichi Kanzaki, Masato Kawashima, Takashi Togo, Omi Katsuse, Noriko Koumitsu, Naoya Aoki, Eizo Iseki, Kenji Kosaka, Kayoko Yamaguchi, Makoto Hashimoto, Ichiro Aoki, Yoshio Hirayasu
The accumulation of α-synuclein (ASyn) has been observed in several lysosomal storage diseases (LSDs) but it remains unclear if ASyn accumulation contributes to LSD pathology. ASyn also accumulates in the neurons of Sandhoff disease (SD) patients and SD model mice (Hexb-/- ASyn+/+ mice). SD is a lysosomal storage disorder caused by the absence of a functional β-subunit on the β-hexosaminidase A and B enzymes, which leads to the accumulation of ganglioside in the central nervous system. Here, we explored the role of accumulated ASyn in the progression of Hexb-/- mice by creating a Hexb-/- ASyn-/- double-knockout mice...
July 21, 2016: Experimental Neurology
Minsook Ye, Hwan-Suck Chung, Chanju Lee, Joo Hyun Song, Insop Shim, Youn-Sub Kim, Hyunsu Bae
α-Synuclein (α-Syn) has a critical role in microglia-mediated neuroinflammation, which leads to the development of Parkinson's disease (PD). Recent studies have shown that bee venom (BV) has beneficial effects on PD symptoms in human patients or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxin-induced PD mice. This study investigated whether treatment with BV-derived phospholipase A2 (bvPLA2) would improve the motor dysfunction and pathological features of PD in human A53T α-Syn mutant transgenic (A53T Tg) mice...
2016: Experimental & Molecular Medicine
Annika Sommer, Tanja Fadler, Eva Dorfmeister, Anna-Carin Hoffmann, Wei Xiang, Beate Winner, Iryna Prots
BACKGROUND: Synucleinopathies comprise a group of neurodegenerative diseases associated with abnormal accumulation of α-synuclein. One of the key factors that contribute to the progression of synucleinopathies is neuroinflammation. However, the role of lymphocytes in synucleinopathies like Parkinson's disease (PD) remains largely unclear. METHODS: To investigate how lymphocytes impact synucleinopathies, human wild-type α-synuclein (WTS) transgenic mice were crossed with mice lacking mature lymphocytes (Rag2(-/-))...
2016: Journal of Neuroinflammation
Changyoun Kim, He-Jin Lee, Eliezer Masliah, Seung-Jae Lee
Synucleinopathies are a collection of neurological diseases that are characterized by deposition of α-synuclein aggregates in neurons and glia. These diseases include Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy. Although it has been increasingly clear that α-synuclein is implicated in the pathogenesis of PD and other synucleinopathies, the precise mechanism underlying the disease process remains to be unraveled. The past studies on how α-synuclein exerts pathogenic actions have focused on its direct, cell-autonomous neurotoxic effects...
June 2016: Experimental Neurobiology
Ana M Catafau, Santiago Bullich
Clinical classifications of neurodegenerative disorders are often based on neuropathology. The term "proteinopathies" includes disorders that have in common abnormal proteins as a hallmark, e.g. amyloidoses, tauopathies, synucleopathies, ubiquitinopathies. Different proteins can also co-exist in the same disease. To further complicate the pathophysiology scenario, not only different proteins, but also cells are believed to play an active role in neurodegeneration, in particular those participating in neuroinflammatory processes in the brain, such as activated microglia and astrocytes...
June 20, 2016: Current Alzheimer Research
Shijun Wang, Chun-Hsien Chu, Mingri Guo, Lulu Jiang, Hui Nie, Wei Zhang, Belinda Wilson, Li Yang, Tessandra Stewart, Jau-Shyong Hong, Jing Zhang
BACKGROUND: Misfolded α-synuclein (α-Syn) aggregates participate in the pathogenesis of synucleinopathies, such as Parkinson's disease. Whereas much is known about how the various domains within full-length α-Syn (FL-α-Syn) contribute to the formation of α-Syn aggregates and therefore to their neurotoxicity, little is known about whether the individual peptides that can be generated from α-syn, possibly as intermediate metabolites during degradation of misfolded α-Syn aggregates, are neurotoxic themselves...
2016: Journal of Neuroinflammation
Oskar Karlsson, Nils Gunnar Lindquist
Melanin is a polyanionic pigment that colors, e.g., the hair, skin and eyes. The pigment neuromelanin is closely related to melanin and is mainly produced in specific neurons of the substantia nigra. Certain drugs and chemicals bind to melanin/neuromelanin and are retained in pigment cells for long periods. This specific retention is thought to protect the cells but also to serve as a depot that slowly releases accumulated compounds and may cause toxicity in the eye and skin. Moreover, neuromelanin and compounds with high neuromelanin affinity have been suggested to be implicated in the development of adverse drug reactions in the central nervous system (CNS) as well as in the etiology of Parkinson's disease (PD)...
August 2016: Archives of Toxicology
Juan Perucho, Ana Gómez, María Paz Muñoz, Justo García de Yébenes, María Ángeles Mena, María José Casarejos
The pathological hallmark of Huntington disease (HD) is the intracellular aggregation of mutant huntingtin (mHTT) in striatal neurons and glia associated with the selective loss of striatal medium-sized spiny neurons. Up to the present, the role of glia in HD is poorly understood and has been classically considered secondary to neuronal disorder. Trehalose is a disaccharide known to possess many pharmacological properties, acting as an antioxidant, a chemical chaperone, and an inducer of autophagy. In this study, we analyzed at an early postnatal development stage the abnormalities observed in striatal glial cell cultures of postnatal R6/1 mice (HD glia), under baseline and stressing conditions and the protective effects of trehalose...
July 2016: Molecular and Cellular Neurosciences
Richard Gordon, Neeraj Singh, Vivek Lawana, Anamitra Ghosh, Dilshan S Harischandra, Huajun Jin, Colleen Hogan, Souvarish Sarkar, Dharmin Rokad, Nikhil Panicker, Vellareddy Anantharam, Anumantha G Kanthasamy, Arthi Kanthasamy
Chronic microglial activation has been linked to the progressive degeneration of the nigrostriatal dopaminergic neurons evidenced in Parkinson's disease (PD) pathogenesis. The exact etiology of PD remains poorly understood. Although both oxidative stress and neuroinflammation are identified as co-contributors in PD pathogenesis, signaling mechanisms underlying neurodegenerative processes have yet to be defined. Indeed, we recently identified that protein kinase C delta (PKCδ) activation is critical for induction of dopaminergic neuronal loss in response to neurotoxic stressors...
September 2016: Neurobiology of Disease
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