Hutchinson-Gilford Progeria Syndrome: Cellular Mechanisms and Therapeutic Perspectives

Cisneros, Bulmaro; García‐Aguirre, Ian; Ita, Marlon De; Arrieta‐Cruz, Isabel; Rosas-Vargas, Haydeé

doi:10.1016/j.arcmed.2023.06.002

Cited by 4 publications

(2 citation statements)

References 119 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mitochondrial homeostasis is associated with progeria phenotypes in HGPS cells, but the mechanistic link remains largely elusive (Cisneros et al., 2023 ). Our results demonstrate that mitophagy defects contribute to the aging hallmarks in HGPS cells.…”

Section: Resultsmentioning

confidence: 99%

“…This mutation leads to the production of progerin, a truncated variant of Lamin A (Ahmed et al., 2018 ). The only drug approved by the US Food and Drug Administration (FDA) for HGPS treatment is Lonafarnib, which targets progerin synthesis (Cisneros et al., 2023 ). However, Lonafarnib causes widespread severe side effects in clinical use, including vomiting, diarrhea, and infection (Gordon et al., 2018 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mitophagy defect mediates the aging‐associated hallmarks in Hutchinson–Gilford progeria syndrome

Sun,

Xu,

et al. 2024

Aging Cell

View full text Add to dashboard Cite

Hutchinson–Gilford progeria syndrome (HGPS) is a rare and fatal disease manifested by premature aging and aging‐related phenotypes, making it a disease model for aging. The cellular machinery mediating age‐associated phenotypes in HGPS remains largely unknown, resulting in limited therapeutic targets for HGPS. In this study, we showed that mitophagy defects impaired mitochondrial function and contributed to cellular markers associated with aging in mesenchymal stem cells derived from HGPS patients (HGPS‐MSCs). Mechanistically, we discovered that mitophagy affected the aging‐associated phenotypes of HGPS‐MSCs by inhibiting the STING‐NF‐ĸB pathway and the downstream transcription of senescence‐associated secretory phenotypes (SASPs). Furthermore, by utilizing UMI‐77, an effective mitophagy inducer, we showed that mitophagy induction alleviated aging‐associated phenotypes in HGPS and naturally aged mice. Collectively, our results uncovered that mitophagy defects mediated the aging‐associated markers in HGPS, highlighted the function of mitochondrial homeostasis in HGPS progression, and suggested mitophagy as an intervention target for HGPS and aging.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mitophagy defect mediates the aging‐associated hallmarks in Hutchinson–Gilford progeria syndrome

Sun,

Xu,

et al. 2024

Aging Cell

View full text Add to dashboard Cite

show abstract

Alexey Olovnikov: theoretical biology beyond the margins

Olovnikov

2023

Biogerontology

View full text Add to dashboard Cite

Interstitial telomeric sequences promote gross chromosomal rearrangement via multiple mechanisms

Rosas Bringas,

Yin,

Yao

et al. 2024

Preprint

View full text Add to dashboard Cite

Telomeric DNA sequences are difficult to replicate. Replication forks frequently pause or stall at telomeres, which can lead to telomere truncation and dysfunction. In addition to being at chromosome ends, telomere repeats are also present at internal locations within chromosomes, known as interstitial telomeric sequences (ITSs). These sequences are unstable and prone to triggering gross chromosomal rearrangements (GCRs). In this study, we quantitatively examined the effect of ITSs on GCR rate inSaccharomyces cerevisiaeusing a genetic assay. We find that GCR rate increases exponentially with ITS length. This increase can be attributed to the telomere repeat binding protein Rap1 impeding DNA replication and a bias of repairing DNA breaks at or distal to the ITS via de novo telomere addition. Additionally, we performed a genome-wide screen for genes that modulate the rate of ITS-induced GCRs. We find that mutation of core components of the DNA replication machinery leads to an increase in GCRs, but many mutants known to increase GCR rate in the absence of an ITS do not significantly affect GCR rate when an ITS is present. We also identified genes that promote the formation of ITS-induced GCRs, including genes with roles in telomere maintenance, nucleotide excision repair, and transcription. Our work thus uncovers multiple mechanisms by which an ITS promotes GCR.Significance statementTelomeric DNA repeats are found at the ends of linear chromosomes where they, together with specialized proteins that bind to them, protect chromosome ends from degradation and unwanted DNA repair activities. Telomeric repeats can also be found at internal locations in the genome, where they are called interstitial telomeric sequences (ITSs). ITSs are prone to breakage and are associated with human diseases. In this study, using baker’s yeast as a model organism, we show that instability at ITSs is driven by multiple factors, and identify genes that either promote or suppress gross chromosomal rearrangements induced by the presence of an ITS.

show abstract

Hutchinson-Gilford Progeria Syndrome: Cellular Mechanisms and Therapeutic Perspectives

Cited by 4 publications

References 119 publications

Mitophagy defect mediates the aging‐associated hallmarks in Hutchinson–Gilford progeria syndrome

Mitophagy defect mediates the aging‐associated hallmarks in Hutchinson–Gilford progeria syndrome

Alexey Olovnikov: theoretical biology beyond the margins

Interstitial telomeric sequences promote gross chromosomal rearrangement via multiple mechanisms

Contact Info

Product

Resources

About