Abstract
Down syndrome (DS) is a genetic disorder caused by trisomy of chromosome 21. Abnormalities in chromosome number have the potential to lead to disruption of the proteostasis network (PN) and accumulation of misfolded proteins. DS individuals suffer from several comorbidities, and we hypothesized that disruption of proteostasis could contribute to the observed pathology and decreased cell viability in DS. Our results confirm the presence of a disrupted PN in DS, as several of its elements, including the unfolded protein response, chaperone system, and proteasomal degradation exhibited significant alterations compared to euploid controls in both cell and mouse models. Additionally, when cell models were treated with compounds that promote disrupted proteostasis, we observed diminished levels of cell viability in DS compared to controls. Collectively our findings provide a cellular-level characterization of PN dysfunction in DS and an improved understanding of the potential pathogenic mechanisms contributing to disrupted cellular physiology in DS. Lastly, this study highlights the future potential of designing therapeutic strategies that mitigate protein quality control dysfunction.
Highlights
IntroductionDown syndrome (DS) is a genetic disorder resulting from the triplication (whole or part) of chromosome 21 (Hsa21)[1]
Down syndrome (DS) is a genetic disorder resulting from the triplication of chromosome 21 (Hsa21)[1]
The presence of basal oxidative stress is a common observation in DS [33,34,35], and this was confirmed in our Lymphoblastoid cell lines (LCL) model by measuring hydrogen peroxide and superoxide production in unstimulated cells (Fig 2A)
Summary
Down syndrome (DS) is a genetic disorder resulting from the triplication (whole or part) of chromosome 21 (Hsa21)[1]. While DS is a form of aneuploidy in humans, it is the only trisomy that does not result in embryonic or early life lethality [2]. Chromosome missegregation has been shown to lead to increased mRNA production and excessive protein formation; linking aneuploidy with a disruption of the proteostasis network and the production of proteotoxic stress [3, 4]. Due to trisomy 21, the DS population is characterized by a variable phenotype with several comorbidities. These comorbidities include seizures [5, 6], leukemia [7], vision problems [8], thyroid dysfunction [9], diabetes [10] and dementia, early onset Alzheimer’s disease (AD) [11]. Errors in protein homeostasis are proposed as candidate mechanisms related to the pathology of the aforementioned comorbidities [12,13,14,15,16,17,18,19,20]
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