PDK4 as a metabolic biomarker of chronic hydrocephalus

TL;DR

The study identifies PDK4 as a key RNA biomarker for chronic hydrocephalus in elderly brains, offering a potential tool for diagnosis and understanding disease mechanisms.

Contribution

PDK4 is newly identified as a prominent RNA biomarker for chronic hydrocephalus, supported by cross-species genomic and transcriptomic analyses.

Findings

PCA and GSEA revealed distinct transcriptional programs in chronic hydrocephalus, with PDK4 as the top-ranked gene.

RT-PCR confirmed PDK4 upregulation in chronic hydrocephalus compared to controls.

Comparative genomics showed conserved transcript length but increased telomeric proximity and A+T content in humans.

Abstract

Chronic hydrocephalus (CH) is a heterogeneous neurological disorder characterized by persistent ventricular enlargement and neurovascular dysfunction in the aging brain. Despite its clinical relevance, genetically anchored RNA biomarkers reflecting CH-associated metabolic and stress-related pathology remain poorly defined.

We performed bulk RNA sequencing of postmortem caudate nucleus tissue from individuals with CH and age-matched neurologically normal controls. Disease-associated transcriptional programs were identified using principal component analysis (PCA), unsupervised hierarchical clustering, and gene set enrichment analysis (GSEA). Key candidate transcripts were validated by RT-PCR. Comparative genomic analyses across mouse, rat, pig, and human genomes examined transcript length, chromosomal positioning, and nucleotide composition.

PCA of the top 1,000 most variable transcripts demonstrated robust separation between CH and controls. Analysis of transcripts ranked 1,001–2,000 independently reproduced disease segregation, indicating distinct transcriptional programs. GSEA revealed significant enrichment of xenobiotic metabolism and oxidative stress pathways, with pyruvate dehydrogenase kinase 4 (PDK4) emerging as the top-ranked gene among ∼40,000 transcripts. RT-PCR confirmed robust PDK4 upregulation. Comparative genomics showed conserved transcript length but increased telomeric proximity and A+T content in humans.

PDK4: is identified as a prominent RNA marker of chronic hydrocephalus in the elderly, providing a neurogenomic foundation for future fluid-based RNA biomarker development.

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