Nuclear protein export pathway in aging therapeutics

Cisneros, Bulmaro; García‐Aguirre, Ian

doi:10.18632/aging.102948

Cited by 3 publications

(7 citation statements)

References 7 publications

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“…If symptoms occur, the disease is usually at an advanced stage. The nuclear protein export mechanism driven by CRM1 is abnormally increased in HGPS fibroblasts because Exportin-1 (XPO1), also known as chromosomal region maintenance 1 (CRM1), is overexpressed [3,[43][44][45]. CRM1 is the primary transport receptor responsible for exporting proteins across the nuclear pore complex (NPC) to the cytoplasm by recognizing the hydrophobic-rich nuclear export signals (NES) present in cargo molecules [3,44].…”

Section: Exportin Crm-1 Inhibitorsmentioning

confidence: 99%

“…CRM1 is the primary transport receptor responsible for exporting proteins across the nuclear pore complex (NPC) to the cytoplasm by recognizing the hydrophobic-rich nuclear export signals (NES) present in cargo molecules [3,44]. CRM-1inhibitors could play a role in HGPS [43][44][45]. Interestingly, many important cellular processes that are altered in HGPS cells are regulated by CRM1-target proteins.…”

Section: Exportin Crm-1 Inhibitorsmentioning

confidence: 99%

“…Additionally, p53 plays a critical role in cellular senescence [46]. Therefore, the use of CRM1 inhibitors could help preserve the nuclear fraction of these and other NES-contained proteins, leading to an improvement in overall cellular physiology [43]. Further research using omics technologies is needed to fully understand the metabolic and molecular pathways underlying the therapeutic effects of CRM1 inhibitors on aging [43][44][45].…”

Section: Exportin Crm-1 Inhibitorsmentioning

confidence: 99%

“…Therefore, the use of CRM1 inhibitors could help preserve the nuclear fraction of these and other NES-contained proteins, leading to an improvement in overall cellular physiology [43]. Further research using omics technologies is needed to fully understand the metabolic and molecular pathways underlying the therapeutic effects of CRM1 inhibitors on aging [43][44][45]. An abnormal increase in nuclear protein export is an early event in the development of cardiac hypertrophy, as HDAC5 is shuttled out of the cardiomyocyte nucleus in a CRM1-dependent manner in response to hypertrophy signaling [3,[43][44][45].…”

Section: Exportin Crm-1 Inhibitorsmentioning

confidence: 99%

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Current Pathophysiological and Therapeutic Options for Children with Hutchinson Gilford Syndrome

Bittmann

2024

Asian J. Pediatr. Res.

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Hutchinson-Gilford-Progeria syndrome (HGPS) cannot, to date, be treated causally. Therapy for affected children focus on alleviating the symptoms, treating secondary diseases and preventing complications such as strokes or heart attacks. Various medications and physiotherapeutic methods are primarily available for this extremely rare pediatric genetic disease. Lonafarnib, a farnesyltransferase inhibitor, has been used for the treatment of progeria in children since 2022, which can extend the life of children with HGPS up to 4 years. Farnesyltransferase inhibitors are able to block an enzyme that is involved in progerin processing. Progerin is the altered protein that occurs in HGPS due to the spelling mistake in the lamin A gene and accumulates within the cell nucleus envelope. As a result, the envelope is weakened and the cell nucleus becomes deformed. The spectrum of therapies includes progerin-targeting strategies on one hand and on therapies to alleviate the tremendous effects by progerin. Research focus on different new targets in the management of HGPS-like the farnesyltransferase inhibitor lonafarnib, Acetyltransferase NAT10-inhibitors, KAT 6a/b and -7 inhibitors, paclitaxel, small molecule ICMT-inhibitors, exportin CRM-1 Inhibitors, progerin-lamin A binding inhibitors (Progerinin), Ghrelin, micro-RNA inhibitors, doxycycline and the regulation of rapamycin complex 1 (mTORC1). This manuscript analyses these new therapeutic targets and pathophysiological aspects in a review manuscript.

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Section: Exportin Crm-1 Inhibitorsmentioning

confidence: 99%

Section: Exportin Crm-1 Inhibitorsmentioning

confidence: 99%

Section: Exportin Crm-1 Inhibitorsmentioning

confidence: 99%

Section: Exportin Crm-1 Inhibitorsmentioning

confidence: 99%

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Current Pathophysiological and Therapeutic Options for Children with Hutchinson Gilford Syndrome

Bittmann

2024

Asian J. Pediatr. Res.

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“…Drugs targeting NRs represent 16% of all drugs approved for sale in the United States in 2019, demonstrating their feasibility as host-directed therapies (HDTs) for disease management ( Ricote and Glass, 2007 ; Santos et al, 2017 ; Boudreaux et al, 2019 ; Zhang et al, 2020 ). NRs are increasingly appreciated for their importance during aging ( Speeckaert et al, 2014 ; Paillasse and de Medina, 2015 ; Cisneros and García-Aguirre, 2020 ; Xu et al, 2020 ). Most past studies have focused on specific NRs in cell lines or murine cells, thus their function and interactions within primary cells and the lung environment are largely unexplored.…”

Section: The Lung Alveolar Environment During Agingmentioning

confidence: 99%

The Impact of Aging on the Lung Alveolar Environment, Predetermining Susceptibility to Respiratory Infections

et al. 2022

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Respiratory infections are one of the top causes of death in the elderly population, displaying susceptibility factors with increasing age that are potentially amenable to interventions. We posit that with increasing age there are predictable tissue-specific changes that prevent the immune system from working effectively in the lung. This mini-review highlights recent evidence for altered local tissue environment factors as we age focusing on increased tissue oxidative stress with associated immune cell changes, likely driven by the byproducts of age-associated inflammatory disease. Potential intervention points are presented.

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Rescue of Mitochondrial Function in Hutchinson-Gilford Progeria Syndrome by the Pharmacological Modulation of Exportin CRM1

Monterrubio-Ledezma

Massieu

Mondragón-Flores

et al. 2023

Cells

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Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder caused by the expression of progerin, a mutant variant of Lamin A. Recently, HGPS studies have gained relevance because unraveling its underlying mechanism would help to understand physiological aging. We previously reported that the CRM1-mediated nuclear protein export pathway is exacerbated in HGPS cells, provoking the mislocalization of numerous protein targets of CRM1. We showed that normalization of this mechanism by pharmacologically inhibiting CRM1 with LMB (specific CRM1 inhibitor), mitigates the senescent phenotype of HGPS cells. Since mitochondrial dysfunction is a hallmark of HGPS, in this study we analyze the effect of LMB on mitochondrial function. Remarkably, LMB treatment induced the recovery of mitochondrial function in HGPS cells, as shown by the improvement in mitochondrial morphology, mitochondrial membrane potential, and ATP levels, which consequently impeded the accumulation of ROS but not mitochondrial superoxide. We provide evidence that the beneficial effect of LMB is mechanistically based on a combinatory effect on mitochondrial biogenesis via upregulation of PGC-1α expression (master transcription cofactor of mitochondrial genes), and mitophagy through the recovery of lysosomal content. The use of exportin CRM1 inhibitors constitutes a promising strategy to treat HGPS and other diseases characterized by mitochondrial impairment.

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Nuclear protein export pathway in aging therapeutics

Cited by 3 publications

References 7 publications

Current Pathophysiological and Therapeutic Options for Children with Hutchinson Gilford Syndrome

Current Pathophysiological and Therapeutic Options for Children with Hutchinson Gilford Syndrome

The Impact of Aging on the Lung Alveolar Environment, Predetermining Susceptibility to Respiratory Infections

Rescue of Mitochondrial Function in Hutchinson-Gilford Progeria Syndrome by the Pharmacological Modulation of Exportin CRM1

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