| 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. |
- Brundin, Patrik, et al.
(författare)
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Neural grafting in Parkinson's disease: problems and possibilities
- 2010
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Ingår i: Progress in Brain Research. - 1875-7855. ; 184, s. 265-294
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Forskningsöversikt (refereegranskat)abstract
- Neural transplantation has emerged as a possible therapy for Parkinson's disease (PD). Clinical studies performed during the 1990s, where dopaminergic neurons derived from the human embryonic brain were transplanted into striatum of patients with PD, provided proof-of-principle that long-lasting therapeutic benefits can be achieved. Subsequent studies, in particular two that followed a double-blind, sham surgery, placebo-control design, showed variable and mostly negative results. They also revealed that some patients develop involuntary movements, so called graft-induced dyskinesias, as side effects. Thus, while nigral transplants clearly work well in select PD cases, the technique needs refinement before it can successfully be performed in a large series of patients. In this review, we describe the clinical neural transplantation trials in PD and the likely importance of factors such as patient selection, trial design, preparation of the donor tissue, and surgical techniques for successful outcome and avoiding unwanted side effects. We also highlight that it was recently found that neuropathological signs typical for PD can appear inside some of the grafted neurons over a decade after surgery. Finally, we discuss future possibilities offered by stem cells as potential sources of dopamine neurons that can be used for transplantation in PD.
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| 3. |
- Brundin, Patrik, et al.
(författare)
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Prion-like transmission of protein aggregates in neurodegenerative diseases.
- 2010
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Ingår i: Nature Reviews. Molecular Cell Biology. - : Springer Science and Business Media LLC. - 1471-0072 .- 1471-0080. ; 11:4, s. 301-307
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Forskningsöversikt (refereegranskat)abstract
- Neurodegenerative diseases are commonly associated with the accumulation of intracellular or extracellular protein aggregates. Recent studies suggest that these aggregates are capable of crossing cellular membranes and can directly contribute to the propagation of neurodegenerative disease pathogenesis. We propose that, once initiated, neuropathological changes might spread in a 'prion-like' manner and that disease progression is associated with the intercellular transfer of pathogenic proteins. The transfer of naked infectious particles between cells could therefore be a target for new disease-modifying therapies.
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| 4. |
- Brundin, Patrik, et al.
(författare)
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Research in motion: the enigma of Parkinson's disease pathology spread.
- 2008
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Ingår i: Nature Reviews Neuroscience. - : Springer Science and Business Media LLC. - 1471-003X .- 1471-0048. ; 9:10, s. 741-745
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Forskningsöversikt (refereegranskat)abstract
- Neuropathological changes in Parkinson's disease progress slowly and spread according to a characteristic pattern. Recent papers have shed light on this progression of pathology by examining the fate of neurons grafted into the brains of patients with Parkinson's disease. Two of these studies demonstrate that grafted healthy neurons can gradually develop the same pathology as host neurons in the diseased brains. According to these studies, implanted neurons developed alpha-synuclein- and ubiquitin-positive Lewy bodies more than a decade after transplantation. We discuss the possible underlying mechanisms and their implications for how pathology spreads in Parkinson's disease.
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| 5. |
- Ciechanover, A, et al.
(författare)
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The ubiquitin proteasome system in neurodegenerative diseases: Sometimes the chicken, sometimes the egg
- 2003
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Ingår i: Neuron. - 0896-6273. ; 40:2, s. 427-446
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Forskningsöversikt (refereegranskat)abstract
- The ubiquitin-proteasome system targets numerous cellular proteins for degradation. In addition, modifications by ubiquitin-like proteins as well as proteins containing ubiquitin-interacting and -associated motifs modulate many others. This tightly controlled process involves multiple specific and general enzymes of the system as well as many modifying and ancillary proteins. Thus, it is not surprising that ubiquitin-mediated degradation/processing/modification regulates a broad array of basic cellular processes. Moreover, aberrations in the system have been implicated, either as a primary cause or secondary consequence, in the pathogenesis of both inherited and acquired neurodegenerative diseases. Recent findings indicate that the system is involved in the pathogenesis of Parkinson's, Alzheimer's, Huntington's, and Prion diseases as well as amyotrophic lateral sclerosis. This raises hopes for a better understanding of the pathogenetic mechanisms involved in these diseases and for the development of novel, mechanism-based therapeutic modalities.
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| 6. |
- Correia, Sofia, et al.
(författare)
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Stem cell-based therapy for Parkinson's disease.
- 2005
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 1365-2060 .- 0785-3890. ; 37:7, s. 487-498
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Forskningsöversikt (refereegranskat)abstract
- Motor dysfunctions in Parkinson's disease are considered to be primarily due to the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Pharmacological therapies based on the principle of dopamine replacement are extremely valuable, but suffer from two main drawbacks: troubling side effects (e.g. dyskinesia) and loss of efficacy with disease progression. Transplantation of embryonic dopaminergic neurons has emerged as a therapeutic alternative. Enthusiasm following the success of the initial open-label trials has been dampened by the negative outcome of double-blind placebo controlled trials. Additionally, the emergence of graft-related dyskinesia indicates that the experimental grafting procedure requires further refinement before it can be developed into a therapy. Shortage of embryonic donor tissue limits large-scale clinical transplantation trials. We review three of the most attractive tissue sources of dopaminergic neurons for cell replacement therapy: human embryonic ventral mesencephalic tissue, embryonic and adult multipotent region-specific stem cells and embryonic stem cells. Recent developments in embryonic stem cell research and on their implications for a future transplantation therapy in Parkinson's disease are described. Finally, we discuss how human embryonic stem cells can be differentiated into dopaminergic neurons, and issues such as the numbers of dopaminergic neurons required for success and the risk for teratoma formation after implantation.
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| 7. |
- Hall, Vanessa, et al.
(författare)
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Restorative cell therapy for Parkinson's disease: A quest for the perfect cell
- 2007
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Ingår i: Seminars in Cell & Developmental Biology. - : Elsevier BV. - 1084-9521. ; 18:6, s. 859-869
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Forskningsöversikt (refereegranskat)abstract
- The development of a cell therapy for the neurodegenerative disorder Parkinson's disease is a realistic ambition. It is pursued by researchers and companies alike, and spans different donor tissue types of embryonic, fetal and adult origins. In this review, we briefly outline the past and current status of research and clinical trials with cell transplantation in Parkinson's disease. We discuss studies on donor tissue derived from embryonic ventral mesencephalon and assess the current research on various forms of stem cells of both embryonic and adult origins in the quest to develop a cell-based therapy for this debilitating movement disorder.
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| 8. |
- Lamberts, Jennifer T, et al.
(författare)
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Spreading of α-synuclein in the face of axonal transport deficits in Parkinson's disease: A speculative synthesis.
- 2015
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 77:Jul 15, s. 276-283
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Forskningsöversikt (refereegranskat)abstract
- Parkinson's disease (PD) is mainly attributed to degeneration of dopamine neurons in the substantia nigra, but its etiopathogenesis also includes impaired protein clearance and axonal transport dysfunction, among others. The spread of α-synuclein (α-syn) aggregates from one neuron to another, in a prion-like manner, is hypothesized to contribute to PD progression. Axonal transport is likely to play a crucial role in this movement of α-syn aggregates between brain regions. At the same time, deficits in axonal transport are suggested to contribute to neuronal failure in PD. In this review, we discuss the apparent contradiction that axonal transport might be essential for disease progression, while dysfunction of axonal transport could simultaneously be a cornerstone of PD pathogenesis. We speculate around models that reconcile how axonal transport can play such a paradoxical role.
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| 9. |
- 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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| 10. |
- Lotharius, Julie, et al.
(författare)
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Impaired dopamine storage resulting from alpha-synuclein mutations may contribute to the pathogenesis of Parkinson's disease.
- 2002
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 11:20, s. 2395-2407
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Forskningsöversikt (refereegranskat)abstract
- Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the inability to initiate, execute and control movement. Neuropathologically, there is a striking loss of dopamine-producing neurons in the substantia nigra pars compacta, accompanied by depletion of dopamine in the striatum. Most forms of PD are sporadic, though in some cases familial inheritance is observed. In the late 1990s, two mutations in the alpha-synuclein gene were linked to rare, autosomal dominant forms of PD. Previously cloned from cholinergic vesicles of the Torpedo electric ray, alpha-synuclein is highly enriched in presynaptic nerve terminals and appears to be involved in synapse maintenance and plasticity. It is expressed ubiquitously in the brain, raising the important question of why dopaminergic neurons are primarily targeted in persons carrying mutations in alpha-synuclein. In this article, we review the current literature on alpha-synuclein and suggest a possible role for this protein in vesicle recycling via its regulation of phospholipase D2, its fatty acid-binding properties, or both. Exogenous application of dopamine, as well as redistribution of vesicular dopamine to the cytoplasm, can be toxic to dopaminergic neurons. Thus, impaired neurotransmitter storage arising from mutations in alpha-synuclein could lead to cytoplasmic accumulation of dopamine. The breakdown of this labile neurotransmitter in the cytoplasm could, in turn, promote oxidative stress and metabolic dysfunction, both of which have been observed in nigral tissue from PD patients.
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