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A label-free SRM workflow identifies a subset of pregnancy specific glycoproteins as potential predictive markers of early-onset pre-eclampsia
Blankley RT, Fisher C, Westwood M, North RA, Baker PN, Walker MJ, Williamson A, Whetton AD, Lin W, McCowan L, Roberts CT, Cooper GJS, Unwin RD, Myers JE
Molecular & Cellular Biomechanics. 2013;12(11):3148-3159.
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Abstract
Abstract. Background: Huntington’s disease (HD) is a neurodegenerative disorder in which the aetiological defect is inherited or spontaneous mutation in the HTT gene, which alters the structure of the corresponding huntingtin protein and initiates a pathogenetic cascade that ultimately leads to or causes dementia. Objective: Here our main objective was to elucidate further the pathogenic processes that underlie neurodegeneration in HD. Methods: By using two-dimensional gel electrophoresis we performed a proteomic case-control study of two brain regions in post-mortem human tissue from seven well-characterized HD patients and eight matched controls. Results: In the middle frontal gyrus we identified twenty-two differentially-expressed proteins whereas by contrast in visual cortex only seven were altered. Twenty of these proteins have not to our knowledge been associated with the pathogenesis of HD before although all functional families implicated have previously been linked to other neurodegenerative diseases. Most of the proteins identified play roles in cell stress responses, apoptosis, metabolic regulation linked to type-2 diabetes, the ubiquitinproteasome system, or protein trafficking/endocytosis. Conclusions: We propose that HTT mutations lead to or cause functional impairment of these pathways and that simultaneous restoration of their functions by targeted pharmacotherapy could ameliorate the signs and symptoms of HD. These studies provide a unique illustration of the interlinked disease processes that underpin/contribute to the pathogenesis of neurodegeneration in a genetically-mediated disorder of protein structure, and provide a signpost towards the design of new therapeutic interventions.