Brain-specific Proteins Decline in the Cerebrospinal Fluid of Humans with Huntington Disease

John J.M. Bergeron,Nathalie Hamel,Andrew D. Strand ,Xiaohong Qian,Line Roy,Kai Stühler ,Qiaojun Fang,Gereon Poschmann,Matthew Fitzgibbon ,Martin W. McIntosh,Helmut E. Meyer,Wantao Ying,Wendy Law,Benoit Houle,Sam Hanash,Fuchu He,Xin Liu,Jiyang Zhang,Vítor Marcel Faça ,Zhao-Bin Zheng ,Damon May ,Blair R. Leavitt

doi:10.1074/mcp.m800231-mcp200

Abstract

We integrated five sets of proteomics data profiling the constituents of cerebrospinal fluid (CSF) derived from Huntington disease (HD)-affected and -unaffected individuals with genomics data profiling various human and mouse tissues, including the human HD brain. Based on an integrated analysis, we found that brain-specific proteins are 1.8 times more likely to be observed in CSF than in plasma, that brain-specific proteins tend to decrease in HD CSF compared with unaffected CSF, and that 81% of brain-specific proteins have quantitative changes concordant with transcriptional changes identified in different regions of HD brain. The proteins found to increase in HD CSF tend to be liver-associated. These protein changes are consistent with neurodegeneration, microgliosis, and astrocytosis known to occur in HD. We also discuss concordance between laboratories and find that ratios of individual proteins can vary greatly, but the overall trends with respect to brain or liver specificity were consistent. Concordance is highest between the two laboratories observing the largest numbers of proteins.

Highlights

Integration with the CSF proteomics data found that 298 proteins/genes of 1574 are tissue markers, among which two major species are brain-specific (ϳ30%) and liver-specific (ϳ33%) (Table IV)
Brain-specific versus those that are not tissue markers both gave a p value Յ0.024, indicating that the consistency of expression changes in HD status measured by a proteomics and genomics approach are significant for brain-specific proteins compared with other proteins (Table V)
Many liver-specific proteins shown to be increased in HD CSF according to the proteomics analysis are not significantly changed based on transcriptional profiling of the brain

Summary

Introduction

Integration with the CSF proteomics data found that 298 proteins/genes of 1574 are tissue markers, among which two major species are brain-specific (ϳ30%) and liver-specific (ϳ33%) (Table IV). 0.0001 0.15 a p value is based on Pearson’s ␹2 test to evaluate the significance of differences of representativeness of brain (liver) proteins in CSF and plasma.

Results

Conclusion