The burden of trisomy 21 disrupts the proteostasis network in Down syndrome

Area of Science:

• Genetics and Molecular Biology
• Cellular Biology
• Biochemistry

Background:

• Down syndrome (DS) is a genetic disorder resulting from trisomy of chromosome 21.
• Chromosomal abnormalities can disrupt the proteostasis network (PN), leading to misfolded protein accumulation.
• PN dysfunction is hypothesized to contribute to DS comorbidities and reduced cell viability.

Purpose of the Study:

• To investigate the role of proteostasis network disruption in Down syndrome.
• To characterize cellular-level PN dysfunction in DS models.
• To explore the link between PN dysfunction and decreased cell viability in DS.

Main Methods:

• Comparison of PN elements (unfolded protein response, chaperone system, proteasomal degradation) in DS and euploid cell and mouse models.
• Assessment of cell viability in DS models treated with compounds exacerbating proteostasis disruption.

Main Results:

• Significant alterations in multiple PN components were observed in DS models compared to controls.
• DS cell models exhibited diminished cell viability when subjected to proteostasis-disrupting conditions.
• These findings confirm PN dysfunction as a cellular characteristic of Down syndrome.

Conclusions:

• Proteostasis network dysfunction is a key cellular feature in Down syndrome.
• Impaired protein quality control contributes to cellular pathology and reduced viability in DS.
• Targeting proteostasis dysfunction presents a potential therapeutic avenue for Down syndrome.