Disrupted Transcriptional Networks by Mutant Atrophin-1 in a Cell Culture Model of Dentatorubral-Pallidoluysian Atrophy.

Dentatorubral-Pallidoluysian Atrophy (DRPLA) is a dominant neurodegenerative disease caused by CAG triplet repeat expansion in ATN1, which encodes the transcriptional co-repressor Atrophin-1. DRPLA features motor, cognitive, and epileptic symptoms and shares pathogenic mechanisms with other polyglutamine (polyQ) disorders, including protein misfolding, impaired autophagy, and transcriptional dysregulation. To understand disease mechanisms, we performed RNA-seq on HEK293T cells stably expressing wild-type or polyQ-expanded ATN1. Cells expressing pathogenic ATN1 exhibited a distinct transcriptomic profile, including disruptions in synaptic organization, extracellular matrix remodeling, ion channel expression, and neurotransmission. Several genes tied to neurodevelopmental, neurodegenerative, and oncogenic pathways were fully activated or silenced. Dysregulated pathways also included inflammation, chromatin remodeling, stress responses, and redox imbalance. Heat shock protein expression changes suggested proteotoxic stress and impaired protein quality control, with some findings conserved in a previously reported Drosophila melanogaster model of DRPLA. These transcriptomic signatures expand our understanding of molecular events related to degeneration in DRPLA and may lead to the identification of therapeutic targets.