Proteomic Profiling of Plasma in Huntington's Disease Reveals Neuroinflammatory Activation and Biomarker Candidates

Dalrymple, Annette; Wild, Edward J.; Joubert, Romain; Sathasivam, Kirupa; Björkqvist, Maria; Petersén, Åsa; Jackson, Graham S.; Isaacs, Jeremy D.; Kristiansen, Mark; Bates, Gillian P.; Leavitt, Blair R.; Keir, Geoff; Ward, Malcolm; Tabrizi, Sarah J.

doi:10.1021/pr0700753

Cited by 203 publications

(170 citation statements)

References 33 publications

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“…Blood samples were obtained from control subjects and patients with genetically diagnosed HD and processed as described previously (10). The patients were clinically assessed by a neurologist experienced in assessment of HD patients.…”

Section: Isolation Of Human Blood Monocytes and Macrophagesmentioning

confidence: 99%

“…Levels of soluble immune markers in serum, such as soluble TNF receptor, IL-2 receptor, and immunoglobulins, are elevated in HD patients (9,10). Plasma samples from HD patients also have increased levels of proinflammatory cytokines and chemokines that correlate with disease progression (11,12), occurring years before the onset of chorea and other HD symptoms.…”

Section: Introductionmentioning

confidence: 99%

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Mutant huntingtin impairs immune cell migration in Huntington disease

Kwan¹,

et al. 2012

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In Huntington disease (HD), immune cells are activated before symptoms arise; however, it is unclear how the expression of mutant huntingtin (htt) compromises the normal functions of immune cells. Here we report that primary microglia from early postnatal HD mice were profoundly impaired in their migration to chemotactic stimuli, and expression of a mutant htt fragment in microglial cell lines was sufficient to reproduce these deficits. Microglia expressing mutant htt had a retarded response to a laser-induced brain injury in vivo. Leukocyte recruitment was defective upon induction of peritonitis in HD mice at early disease stages and was normalized upon genetic deletion of mutant htt in immune cells. Migration was also strongly impaired in peripheral immune cells from pre-manifest human HD patients. Defective actin remodeling in immune cells expressing mutant htt likely contributed to their migration deficit. Our results suggest that these functional changes may contribute to immune dysfunction and neurodegeneration in HD, and may have implications for other polyglutamine expansion diseases in which mutant proteins are ubiquitously expressed.

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Section: Isolation Of Human Blood Monocytes and Macrophagesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mutant huntingtin impairs immune cell migration in Huntington disease

Kwan¹,

et al. 2012

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“…Similar to other neurodegenerative diseases, there is an increase in clusterin levels as well as cytokines IL-6 and IL-8 reported in HD [57]. A small sample proteomic study detected significantly higher levels of prothrombin and haptoglobin which both are proteins associated with inflammatory response [61].…”

Section: Inflammatory Markersmentioning

confidence: 59%

“…Overactivation of myeloid cells, including microglia, and subtle abnormalities of the innate immune system, are among the earliest biochemical changes that have so far been detected in HD patients [15,57]. Most of this work has been carried out in peripheral blood or ex vivo cells [58] but in 2007 Dalrymple and colleagues found that plasma elevations of clusterin were mirrored in CSF from 20 patients and 10 controls in the first report from a CSF collection with dedicated matched contemporaneous healthy controls from the general population, rather than from patients under investigation for other conditions [12].…”

Section: Inflammatory Markersmentioning

confidence: 99%

Cerebrospinal Fluid Biomarkers for Huntington’s Disease

Byrne¹,

Wild

2016

JHD

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Abstract. Cerebrospinal fluid (CSF) is enriched in brain-derived components and represents an accessible and appealing means of interrogating the CNS milieu to study neurodegenerative diseases and identify biomarkers to facilitate the development of novel therapeutics. Many such CSF biomarkers have been proposed for Huntington's disease (HD) but none has been validated for clinical trial use. Across many studies proposing dozens of biomarker candidates, there is a notable lack of statistical power, consistency, rigor and validation. Here we review proposed CSF biomarkers including neurotransmitters, transglutaminase activity, kynurenine pathway metabolites, oxidative stress markers, inflammatory markers, neuroendocrine markers, protein markers of neuronal death, proteomic approaches and mutant huntingtin protein itself. We reflect on the need for large-scale, standardized CSF collections with detailed phenotypic data to validate and qualify much-needed CSF biomarkers for clinical trial use in HD.

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“…Newly identified biomarker candidates that require further investigation include cholesterol metabolites [14] and indirect markers of transcriptional dysregulation such as the histone component H2AFY [15]. Meanwhile clusterin, which our own work revealed as a possible HD plasma biomarker [16], has since been highlighted as a major genetic modifier and possible blood biomarker of Alzheimer's disease [17].…”

Section: Biofluidsmentioning

confidence: 91%