Abstract
Huntington's disease (HD) is a progressive neurodegenerative disease caused by an unstable CAG trinucleotide repeat expansion. The need for biomarkers of onset and progression in HD is imperative, since currently reliable outcome measures are lacking. We used two-dimensional electrophoresis and mass spectrometry to analyze the proteome profiles in cerebrospinal fluid (CSF) of 6 pairs of HD patients and controls. Prothrombin, apolipoprotein A-IV (Apo A-IV) and haptoglobin were elevated in CSF of the HD patients in comparison with the controls. We used western blot as a semi-quantified measurement for prothrombin and Apo A-IV, as well as enzyme linked immunosorbent assay (ELISA) for measurement of haptoglobin, in 9 HD patients and 9 controls. The albumin quotient (Qalb), a marker of blood-brain barrier (BBB) function, was not different between the HD patients and the controls. The ratios of CSF prothrombin/albumin (prothrombin/Alb) and Apo A-IV/albumin (Apo A-IV/Alb), and haptoglobin level were significantly elevated in HD. The ratio of CSF prothrombin/Alb significantly correlated with the disease severity assessed by Unified Huntington's Disease Rating Scale (UHDRS). The results implicate that increased CSF prothrombin, Apo A-IV, and haptoglobin may be involved in pathogenesis of HD and may serve as potential biomarkers for HD.
Highlights
Huntington’s disease (HD) is a progressive neurodegenerative disease with autosomal dominant inheritance, characterized by cognitive decline, movement disorder and different psychiatric manifestations
Since prothrombin was thought to be involved in the inflammatory process through the activation of protease-activated receptors (PARs) and microglia in the central nervous system (CNS), the increased cerebrospinal fluid (CSF) prothrombin hints the inflammatory process in HD
The mechanism of how prothrombin is increased in CSF and how it is involved in the pathogenesis of HD remain to be determined
Summary
Huntington’s disease (HD) is a progressive neurodegenerative disease with autosomal dominant inheritance, characterized by cognitive decline, movement disorder and different psychiatric manifestations. It is caused by an unstable CAG trinucleotide repeat expansion in the gene encoding huntingtin protein [1] resulting in neuronal dysfunction and death predominantly in the striatum and cortex [2]. While many potential beneficial treatments have been reported in cell or/and animal models, reliable pre-symptomatic/ symptomatic biomarkers that can indicate the disease status and test the therapeutic efficacy are lacking. Because cerebrospinal fluid (CSF) is located around and inside the brain, biomarkers originating from it may provide insights into the disease pathophysiology and severity as well as monitoring responses to the preventive, diseasemodifying, and symptomatic therapies
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