Enhanced nuclear protein export in premature aging and rescue of the progeria phenotype by modulation of CRM1 activity

García‐Aguirre, Ian; Alamillo-Iniesta, Alma; Rodríguez‐Pérez, Ruth; Velez-Aguilera, Griselda; Amaro‐Encarnación, Elianeth; Jiménez‐Gutiérrez, Elizabeth; Vásquez-Limeta, Alejandra; Laredo-Cisneros, Marco S.; Morales‐Lázaro, Sara L.; Tiburcio‐Félix, Reynaldo; Ortega, Arturo; Magaña, Jonathan J.; Winder, Steve J.; Cisneros, Bulmaro

doi:10.1111/acel.13002

Cited by 21 publications

(23 citation statements)

References 35 publications

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“…Then, nuclear area and circularity parameters were calculated, as described previously [ 58 ]. The nucleolar area (μm 2 ) was calculated on maxima projection images, using a 3D objects counter, as described previously [ 59 ]. To quantify the fluorescence intensity of γ-H2AX (DNA-damage marker and H3K9me3 (heterochromatin marker) foci, the Find Maxima function from ImageJ was used, as previously described [ 60 ].…”

Section: Methodsmentioning

confidence: 99%

Loss of Dystroglycan Drives Cellular Senescence via Defective Mitosis-Mediated Genomic Instability

Jiménez-Gutiérrez

Mondragón-González

Soto-Ponce

et al. 2020

IJMS

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Nuclear β-dystroglycan (β-DG) is involved in the maintenance of nuclear architecture and function. Nonetheless, its relevance in defined nuclear processes remains to be determined. In this study we generated a C2C12 cell-based DG-null model using CRISPR-Cas9 technology to provide insights into the role of β-DG on nuclear processes. Since DG-null cells exhibited decreased levels of lamin B1, we aimed to elucidate the contribution of DG to senescence, owing to the central role of lamin B1 in this pathway. Remarkably, the lack of DG enables C2C12 cells to acquire senescent features, including cell-cycle arrest, increased senescence-associated-β-galactosidase activity, heterochromatin loss, aberrant nuclear morphology and nucleolar disruption. We demonstrated that genomic instability is one driving cause of the senescent phenotype in DG-null cells via the activation of a DNA-damage response associated with mitotic failure, as shown by the presence of multipolar mitotic spindles, which in turn induced the formation of micronuclei and γH2AX foci (DNA-damage marker), telomere shortening and p53/p21 upregulation. Altogether, these events might ultimately lead to premature senescence, impeding the replication of the damaged genome. In summary, we present evidence supporting a role for DG in protecting against senescence, through the maintenance of proper lamin B1 expression/localization and proper mitotic spindle organization.

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Section: Methodsmentioning

confidence: 99%

Loss of Dystroglycan Drives Cellular Senescence via Defective Mitosis-Mediated Genomic Instability

Jiménez-Gutiérrez

Mondragón-González

Soto-Ponce

et al. 2020

IJMS

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“…The nuclear import pathway mediated by transportin-1 is impaired [54]. CRM1-driven nuclear protein export may be abnormally enhanced [55].…”

Section: Connections Between the Nucleus And The Cytoplasmmentioning

confidence: 99%

Protein structural and mechanistic basis of progeroid laminopathies

2020

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Progeroid laminopathies are characterized by the premature appearance of certain signs of physiological aging in a subset of tissues. They are caused by mutations in genes coding for A-type lamins or lamin-binding proteins. Here, we review how different mutations causing progeroid laminopathies alter protein structure or protein-protein interactions and how these impact on mechanisms that protect cell viability and function. One group of progeroid laminopathies, which includes Hutchinson-Gilford progeria syndrome, is characterized by accumulation of unprocessed prelamin A or variants. These are caused by mutations in the A-type lamin gene (LMNA), altering prelamin A itself, or in ZMPSTE24, encoding an endoprotease involved in its processing. The abnormally expressed farnesylated proteins impact on various cellular processes that may contribute to progeroid phenotypes. Other LMNA mutations lead to the production of nonfarnesylated A-type lamin variants with amino acid substitutions in solventexposed hot spots located mainly in coil 1B and the immunoglobulin fold domain. Dominant missense mutations might reinforce interactions between lamin domains, thus giving rise to excessively stabilized filament networks. Recessive missense mutations in A-type lamins and barrier-toautointegration factor (BAF) causing progeroid disorders are found at the interface between these interacting proteins. The amino acid changes decrease the binding affinity of A-type lamins for BAF, which may contribute to lamina disorganization, as well as defective repair of mechanically induced nuclear envelope rupture. Targeting these molecular alterations in A-type lamins and associated proteins identified through structural biology studies could facilitate the design of therapeutic strategies to treat patients with rare but severe progeroid laminopathies.

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“…The overexpression of a protein exportin-1 or chromosomal region maintenance 1 (CRM1) caused by progerin expression leads to a disbalance in nuclear protein export, which is one of the central regulatory features of progeric phenotype (García-Aguirre et al 2019). Pharmacological inhibition of CRM1 with leptomycin B (LMB) can alleviate almost all significant pathophysiological features of HGPS in the cell viz.…”

Section: Targeting Other Downstream Actions Of Progerinmentioning

confidence: 99%

“…nuclear blebbing, reduced lamin B1 expression, cellular senescence, heterochromatin loss, expansion of nucleoli, etc. Since enhanced nuclear export due to enhanced CRM1 activity is now considered as key converging mechanism in pathological and normal aging, targeting this molecule can significantly attenuate the progression of the disorder (García-Aguirre et al 2019).…”

Section: Targeting Other Downstream Actions Of Progerinmentioning

confidence: 99%

“…There are several other cellular and molecular consequences that result in the pathophysiology of this disease at the cellular and systemic levels. These changes include disruption of nucleocytoplasmic Ran gradient (Kelley et al 2011), disturbance in nuclear export (García-Aguirre et al 2019), alteration in microtubular network (Larrieu et al 2018), defective polarity (Chang et al 2019), reduction in autophagic proteolysis (Lu and Djabali 2018), mitochondrial dysfunction and oxidative stress (Kubben et al 2016;Rivera-Torres et al 2013;Sieprath et al 2015), lowered PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) expression level (Xiong et al 2016), stress in the endoplasmic reticulum (ER) and unfolded protein response (Hamczyk et al 2019), DNA damage (Gonzalo and Kreienkamp 2015;Liu et al 2005), shortening of telomeres (Gonzalez-Suarez et al 2009), defects in purine synthesis (Mateos et al 2018), loss of peripheral heterochromatin (Gesson et al 2016), impaired epigenetic regulation (Shumaker et al 2006), chromatin remodeling (Pegoraro et al 2009), alteration in cell signaling pathways (Aliper et al 2015), inhibition of cell cycle progression and increased apoptosis (Bridger and Kill 2004), leakage of DNA into cytoplasm (Kreienkamp et al 2018), upregulation of inflammatory pathways (Osorio et al 2012), depletion of stem cell reserves for tissue repairing (Rosengardten et al 2011), defects in self-renewal and differentiation capacity of stem cells, and disbalance in the synthesis of extracellular matrix (ECM) components and remodeling enzymes (Csoka et al 2004;Vidak et al 2015).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacotherapy to gene editing: potential therapeutic approaches for Hutchinson–Gilford progeria syndrome

Saxena

Kumar

2020

GeroScience

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Hutchinson-Gilford progeria syndrome (HGPS), commonly called progeria, is an extremely rare disorder that affects only one child per four million births. It is characterized by accelerated aging in affected individuals leading to premature death at an average age of 14.5 years due to cardiovascular complications. The main cause of HGPS is a sporadic autosomal dominant point mutation in LMNA gene resulting in differently spliced lamin A protein known as progerin. Accumulation of progerin under nuclear lamina and activation of its downstream effectors cause perturbation in cellular morphology and physiology which leads to a systemic disorder that mainly impairs the cardiovascular system, bones, skin, and overall growth. Till now, no cure has been found for this catastrophic disorder; however, several therapeutic strategies are under development. The current review focuses on the overall progress in the field of therapeutic approaches for the management/cure of HGPS. We have also discussed the new disease models that have been developed for the study of this rare disorder. Moreover, we have highlighted the therapeutic application of extracellular vesicles derived from stem cells against aging and aging-related disorders and, therefore, suggest the same for the treatment of HGPS.

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Enhanced nuclear protein export in premature aging and rescue of the progeria phenotype by modulation of CRM1 activity

Cited by 21 publications

References 35 publications

Loss of Dystroglycan Drives Cellular Senescence via Defective Mitosis-Mediated Genomic Instability

Loss of Dystroglycan Drives Cellular Senescence via Defective Mitosis-Mediated Genomic Instability

Protein structural and mechanistic basis of progeroid laminopathies

Pharmacotherapy to gene editing: potential therapeutic approaches for Hutchinson–Gilford progeria syndrome

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