Work

Disrupted Transcriptional Networks in Mammalian Cells Stably Over‐Expressing Pathogenic Atrophin‐1

Year: 2025

Type: article

Abstract: 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 over-expressing wild-type or pathogenic 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. The transcriptomic signatures that we describe here expand understanding of the normal functions of ATN1 and the biology of disease of DRPLA.

Source: Journal of Neuroscience Research

DOI: 10.1002/jnr.70089

Authors: Oluwademilade Nuga, Masoumeh Pourhadi, Julia P. Rausch, Sokol V. Todi

Institution: Wayne State University

Language: English

Topic: Genetic Neurodegenerative Diseases

Subfield: Cellular and Molecular Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: bronze

Funders: Wayne State University, Office of the Vice President for Research, Wayne State University, National Institute of Neurological Disorders and Stroke