Intranuclear polyglycine aggregation drives neurodegeneration through epigenetic repression of chromatin accessibility and transcription

ABSTRACT Polyglycine (polyG) proteins translated from expanded GGC trinucleotide repeats are implicated in a growing group of neuromuscular degenerative disorders characterized by intranuclear inclusions, yet the pathogenic importance of aggregate localization and the mechanisms underlying polyG-induced neurodegeneration remain unclear. Here we show that intranuclear polyG aggregates are markedly more pathogenic than cytoplasmic aggregates in cellular and mouse models. Intranuclear aggregation causes greater cell death, more severe behavioral deficits and neuropathology, and earlier mortality. Mechanistically, intranuclear polyG aggregates impair nascent RNA synthesis and are associated with a transcriptionally repressive chromatin state marked by globally reduced chromatin accessibility, decreased H3K27 acetylation, and increased HDAC3 expression across cellular, mouse, and human disease tissue. Using a light-inducible system, we further show that this transcriptional impairment depends on insoluble intranuclear aggregate formation rather than diffuse polyG alone. Pharmacological HDAC inhibition partially restores histone acetylation and transcriptional output and ameliorates behavioral and pathological abnormalities. Together, these findings identify intranuclear polyG aggregates as the more pathologically relevant species and uncover epigenetic repression of chromatin accessibility and transcription as a potentially common mechanism underlying polyG diseases.