| 1. |
- Boza-Serrano, Antonio, et al.
(författare)
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The role of Galectin-3 in α-synuclein-induced microglial activation
- 2014
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 2
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Forskningsöversikt (refereegranskat)abstract
- Background: Parkinson's disease (PD) is the most prevalent neurodegenerative motor disorder. The neuropathology is characterized by intraneuronal protein aggregates of α-synuclein and progressive degeneration of dopaminergic neurons within the substantia nigra. Previous studies have shown that extracellular α-synuclein aggregates can activate microglial cells, induce inflammation and contribute to the neurodegenerative process in PD. However, the signaling pathways involved in α-synuclein-mediated microglia activation are poorly understood. Galectin-3 is a member of a carbohydrate-binding protein family involved in cell activation and inflammation. Therefore, we investigated whether galectin-3 is involved in the microglia activation triggered by α-synuclein. Results: We cultured microglial (BV2) cells and induced cell activation by addition of exogenous α-synuclein monomers or aggregates to the cell culture medium. This treatment induced a significant increase in the levels of proinflammatory mediators including the inducible Nitric Oxide Synthase (iNOS), interleukin 1 Beta (IL-1β) and Interleukin-12 (IL-12). We then reduced the levels of galectin-3 expression using siRNA or pharmacologically targeting galectin-3 activity using bis-(3-deoxy-3-(3-fluorophenyl-1H-1,2,3-triazol-1-yl)-β-D-galactopyranosyl)-sulfane. Both approaches led to a significant reduction in the observed inflammatory response induced by α-synuclein. We confirmed these findings using primary microglial cells obtained from wild-type and galectin-3 null mutant mice. Finally, we performed injections of α-synuclein in the olfactory bulb of wild type mice and observed that some of the α-synuclein was taken up by activated microglia that were immunopositive for galectin-3. Conclusions: We show that α-synuclein aggregates induce microglial activation and demonstrate for the first time that galectin-3 plays a significant role in microglia activation induced by α-synuclein. These results suggest that genetic down-regulation or pharmacological inhibition of galectin-3 might constitute a novel therapeutic target in PD and other synucleinopathies.
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| 2. |
- George, Sonia, et al.
(författare)
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α-Synuclein: The Long Distance Runner.
- 2013
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Ingår i: Brain Pathology. - : Wiley. - 1750-3639 .- 1015-6305. ; 23:3, s. 350-357
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson's disease is characterized by α-synuclein pathology in the form of Lewy bodies and Lewy neurites. Braak et al described the spatial and temporal spread of α-synuclein pathology in Parkinson's disease. Recent experimental studies have demonstrated that α-synuclein can transfer from cell to cell. In this review, we highlight the involvement of α-synuclein in Parkinson's disease and in Braak's staging of Parkinson's disease pathology. We discuss whether a prion-like mechanism of α-synuclein spread might contribute to Parkinson's disease pathology. We describe recent studies investigating cell-to-cell transfer of α-synuclein and focus our review on the long-distance axonal transport of α-synuclein along neurons.
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| 3. |
- Killinger, Bryan A., et al.
(författare)
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The vermiform appendix impacts the risk of developing Parkinson’s disease
- 2018
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 10:465
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Tidskriftsartikel (refereegranskat)abstract
- The pathogenesis of Parkinson’s disease (PD) involves the accumulation of aggregated -synuclein, which has been suggested to begin in the gastrointestinal tract. Here, we determined the capacity of the appendix to modify PD risk and influence pathogenesis. In two independent epidemiological datasets, involving more than 1.6 million individuals and over 91 million person-years, we observed that removal of the appendix decades before PD onset was associated with a lower risk for PD, particularly for individuals living in rural areas, and delayed the age of PD onset. We also found that the healthy human appendix contained intraneuronal -synuclein aggregates and an abundance of PD pathology–associated -synuclein truncation products that are known to accumulate in Lewy bodies, the pathological hallmark of PD. Lysates of human appendix tissue induced the rapid cleavage and oligo-merization of full-length recombinant -synuclein. Together, we propose that the normal human appendix contains pathogenic forms of -synuclein that affect the risk of developing PD.
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| 4. |
- Lema Tomé, Carla, et al.
(författare)
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Inflammation and α-Synuclein's Prion-like Behavior in Parkinson's Disease-Is There a Link?
- 2013
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Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 1559-1182 .- 0893-7648. ; 47:2, s. 561-574
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Forskningsöversikt (refereegranskat)abstract
- Parkinson's disease patients exhibit progressive spreading of aggregated α-synuclein in the nervous system. This slow process follows a specific pattern in an inflamed tissue environment. Recent research suggests that prion-like mechanisms contribute to the propagation of α-synuclein pathology. Little is known about factors that might affect the prion-like behavior of misfolded α-synuclein. In this review, we suggest that neuroinflammation plays an important role. We discuss causes of inflammation in the olfactory bulb and gastrointestinal tract and how this may promote the initial misfolding and aggregation of α-synuclein, which might set in motion events that lead to Parkinson's disease neuropathology. We propose that neuroinflammation promotes the prion-like behavior of α-synuclein and that novel anti-inflammatory therapies targeting this mechanism could slow disease progression.
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| 5. |
- Rey, Nolwen, et al.
(författare)
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Transfer of human α-synuclein from the olfactory bulb to interconnected brain regions in mice.
- 2013
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 126:4, s. 555-573
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Tidskriftsartikel (refereegranskat)abstract
- α-Synuclein (α-syn) is a protein prevalent in neural tissue and known to undergo axonal transport. Intracellular α-syn aggregates are a hallmark of Parkinson's disease (PD). Braak and collaborators have suggested that in people who are destined to eventually develop PD, α-syn aggregate pathology progresses following a stereotypic pattern, starting in the olfactory bulb (OB) and the gut. α-Synuclein aggregates are postulated to spread to interconnected brain regions over several years. Thus, propagation of the pathology via neural pathways can potentially explain how α-syn aggregates spread in PD. We have now studied if α-syn can transfer from the OB to other brain structures through neural connections, by injecting different molecular species of human α-syn (monomers, oligomers, fibrils) into the OB of wild-type mice. We found that non-fibrillar human α-syn is taken up very quickly by OB neurons. Within minutes to hours, it is also found in neurons in structures connected to the OB. Conversely, when we injected bovine serum albumin used as a control protein, we found that it does not diffuse beyond the OB, is rarely taken up by OB cells, and does not transfer to other structures. Taken together, our results show that OB cells readily take up α-syn, and that monomeric and oligomeric, but not fibrillar, forms of α-syn are rapidly transferred to interconnected structures within the timeframe we explored. Our results support the idea that α-syn can transfer along neural pathways and thereby contribute to the progression of the α-syn-related pathology.
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| 6. |
- Reyes, Juan F, et al.
(författare)
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Alpha-synuclein transfers from neurons to oligodendrocytes.
- 2014
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Ingår i: GLIA. - : Wiley. - 1098-1136 .- 0894-1491. ; 62:3, s. 387-398
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Tidskriftsartikel (refereegranskat)abstract
- The origin of α-synuclein (α-syn)-positive glial cytoplasmic inclusions found in oligodendrocytes in multiple system atrophy (MSA) is enigmatic, given the fact that oligodendrocytes do not express α-syn mRNA. Recently, neuron-to-neuron transfer of α-syn was suggested to contribute to the pathogenesis of Parkinson's disease. In this study, we explored whether a similar transfer of α-syn might occur from neurons to oligodendrocytes, which conceivably could explain how glial cytoplasmic inclusions are formed. We studied oligodendrocytes in vitro and in vivo and examined their ability to take up different α-syn assemblies. First, we treated oligodendrocytes with monomeric, oligomeric, and fibrillar forms of α-syn proteins and investigated whether α-syn uptake is dynamin-dependent. Second, we injected the same α-syn species into the mouse cortex to assess their uptake in vivo. Finally, we monitored the presence of human α-syn within rat oligodendroglial cells grafted in the striatum of hosts displaying Adeno-Associated Virus-mediated overexpression of human α-syn in the nigro-striatal pathway. Here, we show that oligodendrocytes take up recombinant α-syn monomers, oligomers and, to a lesser extent, fibrils in vitro in a concentration and time-dependent manner, and that this process is inhibited by dynasore. Further, we demonstrate in our injection model that oligodendrocytes also internalize α-syn in vivo. Finally, we provide the first direct evidence that α-syn can transfer to grafted oligodendroglial cells from host rat brain neurons overexpressing human α-syn. Our findings support the hypothesis of a neuron-to-oligodendrocyte transfer of α-syn, a mechanism that may play a crucial role in the progression and pathogenesis of MSA. GLIA 2014;62:387-398.
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