Regional specialization of upper-layer inhibitory interneuron organization in the human prefrontal cortex.

Prion diseases are a group of fatal, transmissible neurodegenerative disorders that impact a variety of mammalian species, including humans, and are transmissible both within and across specific species (, the bovine spongiform encephalopathy epidemic in the United Kingdom) [,]. Prion formation is characterized by global rearrangement of the host-encoded prion protein, PrP, into the infectious self-templating conformation, PrP []. Accumulation of prions in neuronal tissues leads to gliosis, neuronal dysfunction that results in the onset of clinical signs of disease and inevitable death of the host. Despite decades of study, effective treatments are lacking, and the molecular mechanisms underlying prion disease pathogenesis are not fully understood []. Emerging evidence suggests that epigenetic dysregulation, particularly aberrant DNA methylation, may contribute to prion disease pathology []. Epigenetic mechanisms regulate gene expression without altering the nucleotide sequence, playing essential roles in transcriptional regulation and maintenance of genome stability []. Disruption of these mechanisms has been linked to various diseases, including many cancers and diseases caused by environmental exposures (, air pollution, heavy metals) []. DNA methylation is of particular interest in the context of prion diseases because it plays a well-established role in transcriptional regulation, mediates genome–environment interactions that are important in disease aetiology, and, thanks to genome-wide assays such as nanopore long-read methylation calling, can now be interrogated at scale, making it a compelling target for investigating prion disease pathogenesis [,]. Disrupted methylation patterns can both contribute to disease , Rett Syndrome, cancer) and arise as a consequence of it (, Prader-Willi Syndrome [,]). For example, altered CpG methylation has been implicated in many types of cancer, imprinting disorders, and neurological conditions [,,]. In some prion-like neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS), aberrant methylation has been linked to misfolded protein accumulation and neurotoxicity []. Although prion and prion-like diseases share mechanistic similarities, prion diseases are generally rarer and less extensively studied [].