New Molecular and Organelle Alterations Linked to Down Syndrome Heart Disease

Venegas-Zamora, Leslye; Bravo-Acuña, Francisco; Sigcho, Francisco; Gómez, Wileidy; Bustamante-Salazar, José; Pedrozo, Zully; Parra, Valentina

doi:10.3389/fgene.2021.792231

Cited by 10 publications

(10 citation statements)

References 110 publications

(160 reference statements)

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“…Essentially all who are personally affected by Down syndrome have neurodevelopmental challenges; over half will develop Alzheimer’s Disease in their 40 s and between 8 and 18% have autism 30 – 33 . Approximately 45% of Down syndrome babies (including stillbirths) will have congenital cardiac disease 31 , 34 .…”

Section: Discussionmentioning

confidence: 99%

Involvement of the HERV-derived cell-fusion inhibitor, suppressyn, in the fusion defects characteristic of the trisomy 21 placenta

Sugimoto

Schust

Yamazaki

et al. 2022

Sci Rep

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Suppressyn (SUPYN) is the first host-cell encoded mammalian protein shown to inhibit cell–cell fusion. Its expression is restricted to the placenta, where it negatively regulates syncytia formation in villi. Since its chromosomal localization overlaps with the Down syndrome critical region and the TS21 placenta is characterized by delayed maturation of cytotrophoblast cells and reduced syncytialization, we hypothesized a potential link between changes in SUPYN expression and morphologic abnormalities in the TS21 placenta. Here we demonstrate that an increase in chromosomal copy number in the TS21 placenta is associated with: (1) reduced fusion of cytotrophoblast cells into syncytiotrophoblast in vivo, (2) increased SUPYN transcription, translation and secretion in vivo, (3) increased SUPYN/syncytin-1 receptor degradation in vivo, (4) increased SUPYN transcription and secretion ex vivo, (5) decreased cytotrophoblast cell fusion ex vivo, and (6) reciprocal response of changes in SUPYN and CGB in TS21 placental cells ex vivo. These data suggest direct links between immature placentation in Down syndrome and increased SUPYN. Finally, we report a significant increase in secreted SUPYN concentration in maternal serum in women with pregnancies affected by Down syndrome, suggesting that SUPYN may be useful as an alternate or additional diagnostic marker for this disease.

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Section: Discussionmentioning

confidence: 99%

Involvement of the HERV-derived cell-fusion inhibitor, suppressyn, in the fusion defects characteristic of the trisomy 21 placenta

Sugimoto

Schust

Yamazaki

et al. 2022

Sci Rep

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“…Moreover, mTOR hyperactivity and reduced ATG proteins involved in autophagosome formation contribute to downregulation of mitophagy ( 182 ). Organelle dysfunction could contribute to accelerated aging in patients with Down Syndrome-related CHD ( 183 ).…”

Section: Aging Mechanisms In Congenital Heart Diseasementioning

confidence: 99%

Accelerated Cardiac Aging in Patients With Congenital Heart Disease

Iacobazzi

Alvino

Caputo

et al. 2022

Front. Cardiovasc. Med.

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An increasing number of patients with congenital heart disease (CHD) survive into adulthood but develop long-term complications including heart failure (HF). Cellular senescence, classically defined as stable cell cycle arrest, is implicated in biological processes such as embryogenesis, wound healing, and aging. Senescent cells have a complex senescence-associated secretory phenotype (SASP), involving a range of pro-inflammatory factors with important paracrine and autocrine effects on cell and tissue biology. While senescence has been mainly considered as a cause of diseases in the adulthood, it may be also implicated in some of the poor outcomes seen in patients with complex CHD. We propose that patients with CHD suffer from multiple repeated stress from an early stage of the life, which wear out homeostatic mechanisms and cause premature cardiac aging, with this term referring to the time-related irreversible deterioration of the organ physiological functions and integrity. In this review article, we gathered evidence from the literature indicating that growing up with CHD leads to abnormal inflammatory response, loss of proteostasis, and precocious age in cardiac cells. Novel research on this topic may inspire new therapies preventing HF in adult CHD patients.

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“…[1][2][3][4] Subsequently, failure in organelle functions would trigger disruption in cellular homeostasis leading to different pathophysiological states like cancer, neurodegeneration, metabolic disorders, and cardiovascular diseases. [5][6][7][8][9][10][11] Hence, it is highly imperative to visualize these organelles inside the cells to understand their critical roles in diverse biology to develop next-generation organelle-targeted therapeutics. Towards this end, in the last couple of decades, aggregation-induced emission active probes (AIEgens) gained lots of attention in the scientific community.…”

Section: Introductionmentioning

confidence: 99%

Small Molecule AIEgens for Illuminating Sub‐Cellular Endoplasmic Reticulum, Mitochondria, and Lysosomes**

et al. 2023

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Organelles are the working hubs of the cells. Hence, visualizing these organelles inside the cells is highly important for understanding their roles in pathological states and development of therapeutic strategies. Herein, we report the development of a novel highly substituted oxazoles with modular scaffolds (AIE‐ER, AIE‐Mito, and AIE‐Lyso), which can home into endoplasmic reticulum (ER), mitochondria, and lysosomes inside the cells. These oxazoles showed remarkable aggregation‐induced emission (AIE) property in water and in the solid state due to dual intramolecular H‐bonding, which was confirmed by pH‐ and temperature‐dependent fluorescence studies followed by molecular dynamics (MD) simulations and density functional theory (DFT) calculations. Confocal laser scanning microscopy studies revealed that AIE‐ER, AIE‐Mito, and AIE‐Lyso efficiently homed into ER, mitochondria and lysosomes, respectively, in the HeLa cervical cancer cells and non‐cancerous human retinal pigment epithelial RPE‐1 cells within 3 h without showing any toxicity to the cells with high sub‐cellular photostability. To the best of our knowledge, this is the first report of highly substituted oxazole‐based small molecule AIEgens for organelle imaging. We anticipate these novel AIEgens have promise to image sub‐cellular organelles in different diseased states as well as understanding the inter‐organelle interactions towards the development of novel therapeutics.

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New Molecular and Organelle Alterations Linked to Down Syndrome Heart Disease

Cited by 10 publications

References 110 publications

Involvement of the HERV-derived cell-fusion inhibitor, suppressyn, in the fusion defects characteristic of the trisomy 21 placenta

Involvement of the HERV-derived cell-fusion inhibitor, suppressyn, in the fusion defects characteristic of the trisomy 21 placenta

Accelerated Cardiac Aging in Patients With Congenital Heart Disease

Small Molecule AIEgens for Illuminating Sub‐Cellular Endoplasmic Reticulum, Mitochondria, and Lysosomes**

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