SNARE proteins rescue impaired autophagic flux in Down syndrome

Aivazidis, Stefanos; Jain, Abhilasha; Rauniyar, Abhishek K.; Anderson, Colin C.; Marentette, John; Orlicky, David J.; Fritz, Kristofer S.; Harris, Peter; Siegel, David; Maclean, Kenneth N.; Roede, James R.

doi:10.1371/journal.pone.0223254

Cited by 11 publications

(8 citation statements)

References 86 publications

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“…This is in agreement with the decreased OPA1 expression in DS [24] and its role in cristae remodeling [44,135]. Many studies in cells and tissues of DS patients, and in DS mouse models, reported aberrant hyperactivation of the AKT/mTOR signaling pathway [136][137][138][139], suggesting that imbalance in autophagy flux regulation in DS leads to negative effects on mitochondrial turnover. A deficient mitophagy process could explain the accumulation of damaged mitochondria in DS.…”

Section: Mitochondrial Homeostasis Is Altered In Ds and Agingsupporting

confidence: 81%

Targeting Mitochondrial Network Architecture in Down Syndrome and Aging

Mollo

Cicatiello

Aurilia

et al. 2020

IJMS

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Mitochondria are organelles that mainly control energy conversion in the cell. In addition, they also participate in many relevant activities, such as the regulation of apoptosis and calcium levels, and other metabolic tasks, all closely linked to cell viability. Functionality of mitochondria appears to depend upon their network architecture that may dynamically pass from an interconnected structure with long tubular units, to a fragmented one with short separate fragments. A decline in mitochondrial quality, which presents itself as an altered structural organization and a function of mitochondria, has been observed in Down syndrome (DS), as well as in aging and in age-related pathologies. This review provides a basic overview of mitochondrial dynamics, from fission/fusion mechanisms to mitochondrial homeostasis. Molecular mechanisms determining the disruption of the mitochondrial phenotype in DS and aging are discussed. The impaired activity of the transcriptional co-activator PGC-1α/PPARGC1A and the hyperactivation of the mammalian target of rapamycin (mTOR) kinase are emerging as molecular underlying causes of these mitochondrial alterations. It is, therefore, likely that either stimulating the PGC-1α activity or inhibiting mTOR signaling could reverse mitochondrial dysfunction. Evidence is summarized suggesting that drugs targeting either these pathways or other factors affecting the mitochondrial network may represent therapeutic approaches to improve and/or prevent the effects of altered mitochondrial function. Overall, from all these studies it emerges that the implementation of such strategies may exert protective effects in DS and age-related diseases.

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Section: Mitochondrial Homeostasis Is Altered In Ds and Agingsupporting

confidence: 81%

Targeting Mitochondrial Network Architecture in Down Syndrome and Aging

Mollo

Cicatiello

Aurilia

et al. 2020

IJMS

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“…13 ). Diminished autophagic clearance along with lysosomal impairments have been already reported in DS [ [65] , [66] , [67] , [68] ]. However, the novel aspect of the current study is that CBS inhibition normalizes some of these alterations, thereby further promoting the availability of the ATG3 component, possibly to facilitate the formation of functional complexes of the autophagic machinery ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Role of the cystathionine β-synthase / H2S pathway in the development of cellular metabolic dysfunction and pseudohypoxia in down syndrome

Panagaki¹,

Pecze²,

Randi³

et al. 2022

Redox Biology

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“…Aneuploidy-associated stress is known to stimulate the accumulation of autophagosomal cargo such as protein aggregates within lysosomes 15 . Importantly, impaired autophagic flux, which is accompanied by elevated p62, has been observed in DS cells 56 . It was reported that 4-PBA alleviates ER stress and ER stress-associated autophagy 57,58 by suppressing the AKT/ TSC/mTOR signalling pathway 54 .…”

Section: Discussionmentioning

confidence: 96%

4-Phenylbutyrate ameliorates apoptotic neural cell death in Down syndrome by reducing protein aggregates

Hirata

Nambara

Kawatani

et al. 2020

Sci Rep

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Individuals with Down syndrome (DS) commonly show unique pathological phenotypes throughout their life span. Besides the specific effects of dosage-sensitive genes on chromosome 21, recent studies have demonstrated that the gain of a chromosome exerts an adverse impact on cell physiology, regardless of the karyotype. Although dysregulated transcription and perturbed protein homeostasis are observed in common in human fibroblasts with trisomy 21, 18, and 13, whether and how this aneuploidy-associated stress acts on other cell lineages and affects the pathophysiology are unknown. Here, we investigated cellular stress responses in human trisomy 21 and 13 neurons differentiated from patient-derived induced pluripotent stem cells. Neurons of both trisomies showed increased vulnerability to apoptotic cell death, accompanied by dysregulated protein homeostasis and upregulation of the endoplasmic reticulum stress pathway. In addition, misfolded protein aggregates, comprising various types of neurodegenerative disease-related proteins, were abnormally accumulated in trisomic neurons. Intriguingly, treatment with sodium 4-phenylbutyrate, a chemical chaperone, successfully decreased the formation of protein aggregates and prevented the progression of cell apoptosis in trisomic neurons. These results suggest that aneuploidy-associated stress might be a therapeutic target for the neurodegenerative phenotypes in DS. Down syndrome (DS) is the most common genetic chromosomal disorder, affecting approximately one in 700-800 newborns 1. All individuals with DS exhibit cognitive and learning deficits, with broad variation in phenotypes and severities 2. Studies using in vitro and in vivo experiments with postmortem brains, neural stem/ progenitor cells (NPCs), or induced pluripotent stem cells (iPSCs) derived from DS patients and DS mouse models have shown various levels of neuropathology, including reduced neurogenesis, impaired neuronal maturation, and accelerated neural cell death. These features arise from the extra copy of human chromosome 21 (Hsa21), and specific DS phenotypes are generally thought to be derived from the increased expression of a specific subset of dosage-sensitive genes on Hsa21 3. Based on this 'gene dosage imbalance' hypothesis, multiple studies have been conducted to identify the genes responsible for impaired neural development 4-6. Human neural progenitors isolated from foetal brains with DS show vulnerability to oxidative stress and preference for gliogenesis, which is accompanied by elevated expression levels of S100B and APP genes 7. The DYRK1A gene is reported to affect the differentiation of mouse cortical NPCs and play a critical role in brain morphogenesis 8. The administration

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SNARE proteins rescue impaired autophagic flux in Down syndrome

Cited by 11 publications

References 86 publications

Targeting Mitochondrial Network Architecture in Down Syndrome and Aging

Targeting Mitochondrial Network Architecture in Down Syndrome and Aging

Role of the cystathionine β-synthase / H2S pathway in the development of cellular metabolic dysfunction and pseudohypoxia in down syndrome

4-Phenylbutyrate ameliorates apoptotic neural cell death in Down syndrome by reducing protein aggregates

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