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

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Dentatorubral-pallidoluysian atrophy (DRPLA) is a dominant neurodegenerative disorder.
• It stems from CAG triplet repeat expansion in the ATN1 gene, encoding Atrophin-1.
• DRPLA shares mechanisms with other polyglutamine disorders, such as protein misfolding and impaired autophagy.

Purpose of the Study:

• To investigate the molecular mechanisms underlying DRPLA.
• To identify transcriptomic changes associated with pathogenic ATN1 expression.

Main Methods:

• RNA sequencing (RNA-seq) was performed on HEK293T cells.
• Cells were engineered to stably over-express either wild-type or pathogenic ATN1.

Main Results:

• Pathogenic ATN1 expression caused distinct transcriptomic alterations.
• Disruptions were observed in synaptic organization, extracellular matrix, ion channels, and neurotransmission.
• Dysregulated pathways included inflammation, chromatin remodeling, stress responses, and redox imbalance, with altered heat shock protein expression indicating proteotoxic stress.

Conclusions:

• The study identified significant transcriptomic signatures in DRPLA.
• These findings enhance the understanding of Atrophin-1's normal function and DRPLA pathogenesis.
• Conserved findings in a Drosophila model suggest shared disease mechanisms.