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

Aivazidis, Stefanos; Coughlan, Christina; Rauniyar, Abhishek K.; Jiang, Hua; Liggett, L. Alexander; Maclean, Kenneth N.; Roede, James R.

doi:10.1371/journal.pone.0176307

Cited by 55 publications

(53 citation statements)

References 102 publications

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“…These findings inspired our interest in investigating possible PN dysfunction and the presence of a dysregulated protein quality control system in DS. Recently, our laboratory has reported a dysfunctional PN in DS models with increased presence of ER stress, limited chaperone expression after heat stress and increased sensitivity to proteotoxic compounds (8). Our findings here build upon this previous research and focus on further characterizing the possible pathogenic role of PN disruption via the study of the autophagic process in DS models.…”

Section: Discussionsupporting

confidence: 72%

“…Previous research from our laboratory and others has revealed the presence of a dysfunctional proteostasis network (PN) in DS cell models, characterized by several markers of disrupted proteostasis (8)(9)(10)(11)(12). More specifically, DS cells exhibit basal endoplasmic reticulum (ER) stress, increased abundance of polyubiquitinated proteins and decreased proteasomal degradation.…”

Section: Introductionmentioning

confidence: 99%

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Down syndrome fibroblasts exhibit diminished autophagic clearance and endosomal dysfunction after serum starvation

Aivazidis

Jain

Anderson

et al. 2018

Preprint

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Down syndrome (DS) is a genetic disorder caused by trisomy of chromosome 21 (Tri21). This unbalanced karyotype has the ability to produce proteotoxic stress and dysfunction of the proteostasis network (PN), which are mechanistically associated with several comorbidities found in the DS phenotype. Autophagy is the cellular process responsible for bulk protein degradation and its impairment could negatively impact protein quality control. Based on our previous observations of PN disruption in DS, we investigated possible dysfunction of the autophagic machinery in human DS fibroblasts. Both euploid (CTL) and DS fibroblasts induced autophagy successfully through serum starvation (SS), as evidenced by increased LC3-II abundance in CTL and DS. However, DS cells displayed evidence of autophagolysosome (AL) accumulation and impaired clearance of autophagosome cargo, e.g. accumulation of p62 and NBR1. Similar observations were also present in DS cells from multiple differentiation stages, implicating impeded autophagic degradation as a possible early pathologic mechanism in DS. Lysosomal pH and cathepsin B proteolytic activity were found to not differ in CTL and DS fibroblasts after SS, indicating that lysosomal dysfunction did not appear to contribute to unsuccessful autophagic clearance. Based on these results, we hypothesized that possible interference of the endosomal system with autophagy results in autophagosome fusion with endosomal vesicles and negatively impacts degradation. Consistent with this hypothesis, we observed increased abundance of the recycling endosome marker, Rab11, after SS in DS fibroblasts. Further, colocalization of autophagosome markers with resident proteins of early endosomes, late endosomes and recycling endosomes (Rab11) further support our hypothesis. In summary, our work is consistent with impairment of autophagic flux and general PN dysfunction as candidate mechanisms for pathology in DS.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Down syndrome fibroblasts exhibit diminished autophagic clearance and endosomal dysfunction after serum starvation

Aivazidis

Jain

Anderson

et al. 2018

Preprint

Self Cite

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“…Consistently, these cells were hypersensitive to heat or ER stressors. Unlike control euploid cells, in which expression of heat shock proteins (HSP) increased in response to heat shock stress, HSP90 and HSP70 expression showed no changes under a moderate heat shock in aneuploid cells (Aivazidis et al, 2017). This is likely due to a pre-existing stress state in the aneuploid cells that compromises the induction of HSP expression.…”

Section: Aneuploidy-associated Stressmentioning

confidence: 92%

Cellular Stress Associated with Aneuploidy

et al. 2018

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Aneuploidy, chromosome stoichiometry that deviates from exact multiples of the haploid compliment of an organism, exists in eukaryotic microbes, several normal human tissues, and the majority of solid tumors. Here, we review the current understanding about the cellular stress states that may result from aneuploidy. The topics of aneuploidy-induced proteotoxic, metabolic, replication, and mitotic stress are assessed in the context of the gene dosage imbalance observed in aneuploid cells. We also highlight emerging findings related to the downstream effects of aneuploidy-induced cellular stress on the immune surveillance against aneuploid cells.

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“…Disruption of the proteostasis network and accumulation of misfolded proteins occur as a result of an abnormality in the number of chromosome 21 [12]. Errors in protein homeostasis could contribute to the observed pathology and decreased cell viability in children with Down syndrome [13].…”

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confidence: 99%