| 1. |
- Kwan, Wanda, et al.
(författare)
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Bone Marrow Transplantation Confers Modest Benefits in Mouse Models of Huntington's Disease.
- 2012
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Ingår i: The Journal of Neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 32:1, s. 133-142
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is caused by an expanded polyglutamine tract in the protein huntingtin (htt). Although HD has historically been viewed as a brain-specific disease, htt is expressed ubiquitously, and recent studies indicate that mutant htt might cause changes to the immune system that could contribute to pathogenesis. Monocytes from HD patients and mouse models are hyperactive in response to stimulation, and increased levels of inflammatory cytokines and chemokines are found in pre-manifest patients that correlate with pathogenesis. In this study, wild-type (WT) bone marrow cells were transplanted into two lethally irradiated transgenic mouse models of HD that ubiquitously express full-length htt (YAC128 and BACHD mice). Bone marrow transplantation partially attenuated hypokinetic and motor deficits in HD mice. Increased levels of synapses in the cortex were found in HD mice that received bone marrow transplants. Importantly, serum levels of interleukin-6, interleukin-10, CXC chemokine ligand 1, and interferon-γ were significantly higher in HD than WT mice but were normalized in mice that received a bone marrow transplant. These results suggest that immune cell dysfunction might be an important modifier of pathogenesis in HD.
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| 2. |
- Wild, Edward, et al.
(författare)
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Abnormal peripheral chemokine profile in Huntington's disease.
- 2011
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Ingår i: PLoS Currents. - 2157-3999. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. Immune activation is a well-established feature of the HD brain and we have previously demonstrated a widespread, progressive innate immune response detectable in plasma throughout the course of HD. In the present work we used multiplex ELISA to quantify levels of chemokines in plasma from controls and subjects at different stages of HD. We found an altered chemokine profile tracking with disease progression, with significant elevations of five chemokines (eotaxin-3, MIP-1β, eotaxin, MCP-1 and MCP-4) while three (eotaxin-3, MIP-1β and eotaxin) showed significant linear increases across advancing disease stages. We validated our results in a separate sample cohort including subjects at different stages of HD. Here we saw that chemokine levels (MCP-1 and eotaxin) correlated with clinical scores. We conclude that, like cytokines, chemokines may be linked to the pathogenesis of HD, and that immune molecules may be valuable in tracking and exploring the pathogenesis of HD.
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| 3. |
- Gaughwin, Philip, et al.
(författare)
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Hsa-miR-34b is a plasma-stable microRNA that is elevated in pre-manifest Huntington's disease
- 2011
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 20:11, s. 2225-2237
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is a devastating, neurodegenerative condition, which lacks effective treatment. Normal Huntingtin (HTT) and mutant Huntingtin (mHTT) are expressed in multiple tissues and can alter transcription of microRNAs (miRs). Importantly, miRs are present in a bio-stable form in human peripheral blood plasma and have recently been shown to be useful biomarkers in other diseases. We therefore sought to identify potential miR biomarkers of HD that are present in, and have functional consequences for, neuronal and non-neuronal tissues. In a cell line over-expressing mHTT-Exon-1, miR microarray analysis was used to identify candidate miRs. We then examined their presence and bio-stability in control and HD plasma. We found that miR-34b is significantly elevated in response to mHTT-Exon-1, and its blockade alters the toxicity of mHTT-Exon-1 in vitro. We also show that miR-34b is detectable in plasma from small input volumes and is insensitive to freeze-thaw-induced RNA degradation. Interestingly, miR-34b is significantly elevated in plasma from HD gene carriers prior to symptom onset. This is the first study suggesting that plasma miRs might be used as biomarkers for HD.
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| 4. |
- Gram, Magnus, et al.
(författare)
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Increased levels of hemoglobin and alpha1-microglobulin in Huntington's disease.
- 2012
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Ingår i: Frontiers in Bioscience (Elite Edition). - 1945-0508. ; 4, s. 950-957
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Tidskriftsartikel (refereegranskat)abstract
- Hemoglobin released from damaged erythrocytes is a major pro-oxidant, generator of free radicals and inflammatory mediator. Huntington's disease is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities, in which oxidative stress has been suggested as a possible pathogenic mechanism. In the present work we have investigated levels of hemoglobin and markers of oxidative damage, including the heme- and radical-scavenger alpha1-microglobulin, in plasma and urine samples from two separate sample cohorts, including controls, premanifest gene carriers and subjects at different stages of Huntington's disease. The results show statistically significant increased levels of hemoglobin and alpha1-microglobulin in Huntington's disease urine samples. Interestingly, urine hemoglobin levels correlate with clinical severity. The results suggest that hemolysis may be linked to the pathogenesis of Huntington's disease and that assay of hemoglobin and alpha1-microglobulin may provide biomarkers that are linked to biologically relevant processes.
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| 5. |
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| 6. |
- Silajdzic, Edina, et al.
(författare)
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A Critical Evaluation of Inflammatory Markers in Huntington’s Disease Plasma
- 2013
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Ingår i: Journal of Huntington's disease. - 1879-6397. ; 2:1, s. 125-134
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Huntington’s Disease (HD) is a hereditary, progressive neurodegenerative disorder characterised by both neurological and systemic symptoms. In HD, immune changes can be observed before the onset of overt clinical features raising the possibility that immune markers in plasma could be used to track disease progression. It has previously been demonstrated that a widespread, progressive innate immune response is detectable in plasma throughout the course of HD. OBJECTIVE: The aim of the present study was to investigate the potential of several components of innate immunity as plasma biomarkers in HD. METHODS: We utilised antibody-based detection technologies as well as mass spectrometric quantification, multiple reaction monitoring (MRM-MS). RESULTS: Levels of several markers previously described as altered in HD, such as clusterin, complement component 4, complement component 9 and α-2 macroglobulin did not differ between healthy controls and HD subjects as measured by Luminex, ELISA or MRM-MS. C-reactive protein was decreased in early HD, while the other immune markers tested were unaltered. CONCLUSIONS: Of the immune markers tested in this study, none showed potential to track with HD disease progression.
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| 7. |
- Traeger, Ulrike, et al.
(författare)
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HTT-lowering reverses Huntington's disease immune dysfunction caused by NF kappa B pathway dysregulation
- 2014
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 137, s. 819-833
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The peripheral innate immune system contributes to Huntington's disease pathogenesis and has been targeted successfully to modulate disease progression, but mechanistic understanding relating this to mutant huntingtin expression in immune cells has been lacking. Here we demonstrate that human Huntington's disease myeloid cells produce excessive inflammatory cytokines as a result of the cell-intrinsic effects of mutant huntingtin expression. A direct effect of mutant huntingtin on the NF kappa B pathway, whereby it interacts with IKK gamma, leads to increased degradation of I kappa B and subsequent nuclear translocation of RelA. Transcriptional alterations in intracellular immune signalling pathways are also observed. Using a novel method of small interfering RNA delivery to lower huntingtin expression, we show reversal of disease-associated alterations in cellular function-the first time this has been demonstrated in primary human cells. Glucan-encapsulated small interfering RNA particles were used to lower huntingtin levels in human Huntington's disease monocytes/macrophages, resulting in a reversal of huntingtin-induced elevated cytokine production and transcriptional changes. These findings improve our understanding of the role of innate immunity in neurodegeneration, introduce glucan-encapsulated small interfering RNA particles as tool for studying cellular pathogenesis ex vivo in human cells and raise the prospect of immune cell-directed HTT-lowering as a therapeutic in Huntington's disease.
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