Brain-specific proteins decline in the cerebrospinal fluid of humans with Huntington disease

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.

Fig. 1.

Number of total protein groups and genes identified and quantitated by different numbers of methods. Protein groups are in solid bars, and genes are in empty bars.

Fig. 2.

Patterns of tissue-specific proteins in CSF. A, proteins were sorted in descending order by spectral counts that reflect the relative concentration in CSF with highest concentrations at the top. B, proteins were sorted in descending order by sums of z-scores that indicate the trends of changes in HD-affected individuals relative to control with the most increasing one at the top. Red, brain-specific proteins; green, liver-specific proteins; black, muscle- and heart-specific proteins; white, other tissue-specific proteins.

Fig. 3.

Correlations of relative protein abundance ratios of two disease statuses among different proteomics methods. Both axes are the following three ratios on a logarithm scale based on different quantitation methods: HD-early/control (A), HD-mid/control (B), and HD-mid/HD-early (C).