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Does chromatin modulation provide the first wet biomarker for Huntington's disease?

The search for biomarkers is a hot topic in nearly all neurodegenerative disorders. In Huntington’s disease (HD), biomarkers may be useful in identifying promising drugs in preclinical development and enable proof of concept in earlystage clinical development. The unique access to large groups of clinically asymptomatic HD gene carriers makes it feasible to conduct clinical trials in subjects prior to disease manifestation by delaying or preventing symptom onset. This makes HD a particularly interesting model disease and further emphasizes the special need for biomarkers in this condition. It also stresses the need for a biomarker that, first, can be obtained repeatedly with low risk from peripheral tissues and, second, should ideally be associated with a mechanism known to be involved in the pathology of the disease. In their work, Hu et al identified a dynamic regulator of chromatic plasticity H2A histone family, member Y (H2AFY) as an interesting candidate biomarker for HD. In a systematic transcriptome-wide analysis, H2AFY was identified as 1 of several candidate genes expressed differentially in HD. Because transcriptional dysregulation has been suggested to be involved in HD pathology, the authors prioritized further evaluation of H2AFY. Upregulation of H2AFY mRNA could be reproduced in 2 independent validation studies. The first cross-sectional study confirmed the increased expression of H2AFY in a larger group of manifest HD patients and extended the findings to a group of premanifest HD gene carriers. A second longitudinal case–control study confirmed increased levels of H2AFY in subjects for up to 3 years. Expression of H2AFYencoded MacroH2A1 was increased in brains of patients with early-stage HD the same as in transgenic and knock-in mouse models of HD. Ideally, a biomarker should also respond to therapy. The authors treated tgHD R6/2 mice with sodium phenylbutyrate, a histone-deacetylase inhibitor, which was previously shown to suppress mutant huntingtin-induced neurodegeneration in animal models. Via semiquantitative Western blots, they showed reduction of MacroH2A1 expression, suggesting a response to therapy. Interestingly the authors had access to blood samples of a subgroup of HD patients enrolled in the randomized, double-blind, placebo-controlled phase II study Phenylbutyrate Development for Huntington’s Disease (PHEND-HD). Analysis of mRNA levels by qPCR revealed downregulation of H2AFY over time in the treatment arm during the placebo phase of the trial and in all subjects during the open-label phase. These observations are suggestive of a pharmacodynamic response of H2AFY to therapy. Clearly, these findings need to be replicated independently in larger cohorts, and as discussed by the authors, the mechanism by which H2AFY is regulated by mutant htt needs to be investigated. However, as pointed out in an accompanying editorial by Michelle Ehrlich and Sam Gandy, ‘‘Genetics and genomics are at their most powerful when they point to molecules and pathways that would not have been contemplated relying upon logic alone.’’ The thorough experimental approach in different biological systems certainly is intriguing and warrants further investigation into H2AFY in HD.