Nuclear membrane ruptures underlie the vascular pathology in a mouse model of Hutchinson-Gilford progeria syndrome

Kim, Paul H.; Chen, Natalie; Heizer, Patrick J.; Tu, Yiping; Weston, Thomas A.; Fong, Jared L.-C.; Gill, Navjot Kaur; Rowat, Amy C.; Young, Stephen G.; Fong, Loren G.

doi:10.1172/jci.insight.151515

Cited by 26 publications

(34 citation statements)

References 54 publications

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“…It is tempting to suggest that since progeric LaA, either LaA Δ50, K542N or L647R and progeric BAF A12T all share a defect in lamin recruitment to nuclear ruptures that this may be an underlying mechanism of disease. This concept could be further supported by the recent studies suggesting that nuclear ruptures do pathologically occur in a mouse model of progeria [ 72 ]. However, the situation is clearly more nuanced and complicated.…”

Section: Discussionmentioning

confidence: 68%

“…Recent evidence suggests nuclear rupture may be an underlying mechanism of the vascular pathology seen in a HGPS mouse model, in which ruptures were identified in aortic smooth muscle cells preceding the loss of these cells in the HGPS mice [ 72 ]. Furthermore, perturbation of the LINC complex in this HGPS mouse model alleviated the loss of the aortic smooth muscle cells by disrupting the cytoskeletal force transmission to the nucleus [ 73 ].…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of A-Type Lamin Targeting to Nuclear Ruptures Are Disrupted in LMNA- and BANF1-Associated Progerias

Sears

Roux

2022

Cells

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Mutations in the genes LMNA and BANF1 can lead to accelerated aging syndromes called progeria. The protein products of these genes, A-type lamins and BAF, respectively, are nuclear envelope (NE) proteins that interact and participate in various cellular processes, including nuclear envelope rupture and repair. BAF localizes to sites of nuclear rupture and recruits NE-repair machinery, including the LEM-domain proteins, ESCRT-III complex, A-type lamins, and membranes. Here, we show that it is a mobile, nucleoplasmic population of A-type lamins that is rapidly recruited to ruptures in a BAF-dependent manner via BAF’s association with the Ig-like β fold domain of A-type lamins. These initially mobile lamins become progressively stabilized at the site of rupture. Farnesylated prelamin A and lamin B1 fail to localize to nuclear ruptures, unless that farnesylation is inhibited. Progeria-associated LMNA mutations inhibit the recruitment affected A-type lamin to nuclear ruptures, due to either permanent farnesylation or inhibition of BAF binding. A progeria-associated BAF mutant targets to nuclear ruptures but is unable to recruit A-type lamins. Together, these data reveal the mechanisms that determine how lamins respond to nuclear ruptures and how progeric mutations of LMNA and BANF1 impair recruitment of A-type lamins to nuclear ruptures.

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Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Mechanisms of A-Type Lamin Targeting to Nuclear Ruptures Are Disrupted in LMNA- and BANF1-Associated Progerias

Sears

Roux

2022

Cells

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“…The loss of NE integrity has indeed been observed in vitro in cells from laminopathy patients [71], in cancer cells [72] and in cells in which the NE had been weakened by viral infection or viral proteins expression [73,74]. In vivo, NE ruptures have been observed as cells experience confined migration through dense tissues [6,7,75], at the invasive edge of human tumours [76] and in aortic smooth muscle cells of a mouse progeria model [77]. In this context, NE ruptures can occur when pressure on the nuclear envelope becomes so high that this leads to a transient loss of NE integrity.…”

Section: Nuclear Envelope Blebs and Rupturesmentioning

confidence: 89%

Current Methods and Pipelines for Image-Based Quantitation of Nuclear Shape and Nuclear Envelope Abnormalities

Janssen

Breusegem

Larrieu

2022

Cells

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Any given cell type has an associated “normal” nuclear morphology, which is important to maintain proper cellular functioning and safeguard genomic integrity. Deviations from this can be indicative of diseases such as cancer or premature aging syndrome. To accurately assess nuclear abnormalities, it is important to use quantitative measures of nuclear morphology. Here, we give an overview of several nuclear abnormalities, including micronuclei, nuclear envelope invaginations, blebs and ruptures, and review the current methods used for image-based quantification of these abnormalities. We discuss several parameters that can be used to quantify nuclear shape and compare their outputs using example images. In addition, we present new pipelines for quantitative analysis of nuclear blebs and invaginations. Quantitative analyses of nuclear aberrations and shape will be important in a wide range of applications, from assessments of cancer cell anomalies to studies of nucleus deformability under mechanical or other types of stress.

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“…Understanding the mechanisms underlying progerin toxicity in the vasculature is crucial to find therapeutic strategies that ameliorate CVD in HGPS patients. VSMC are extremely sensitive to progerin accumulation, which can affect vessel wall integrity and repair, and play a significant role in CVD in HGPS (Hamczyk et al, 2018; Kim et al, 2021). This work provides new insights into progerin-induced vascular disease.…”

Section: Discussionmentioning

confidence: 99%

Progerin triggers a phenotypic switch in vascular smooth muscle cells that causes replication stress and an aging-associated secretory signature

Coll-Bonfill

Mahajan

Lin

et al. 2022

Preprint

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Hutchinson Gilford Progeria Syndrome is a premature aging disease caused by LMNA gene mutation and the production of a truncated lamin A protein, named progerin, that elicits cellular and organismal toxicity. Progerin accumulates in the vasculature, being especially toxic for vascular smooth muscle cells (VSMC). Patients' autopsies show that vessel stiffening, and aortic atherosclerosis is accompanied by VSMC depletion in the medial layer, altered extracellular matrix (ECM), and thickening of the adventitial layer. Mechanisms whereby progerin causes massive VSMC loss and vessel alterations remain poorly understood. Mature VSMC retain phenotypic plasticity and can switch to a synthetic/proliferative phenotype. Here we show that progerin expression in human and mouse VSMC causes a switch towards the synthetic/proliferative phenotype. This switch elicits some level of replication stress in normal cells, which is exacerbated in the presence of progerin, leading to telomere fragility, genomic instability, and ultimately VSMC death. Importantly, calcitriol prevents replication stress, telomere fragility, and genomic instability, reducing VSMC death. In addition, RNAseq analysis shows induction of a profibrotic and proinflammatory aging-associated secretory phenotype upon progerin expression in human primary VSMC. Our data suggest that phenotypic switch-induced replication stress might be an underlying cause of VSMC loss in progeria, which together with loss of contractile features and gain of profibrotic and proinflammatory signatures contribute to vascular stiffness in HGPS. Preventing the phenotypic switch-induced replication stress with compounds such as calcitriol might ameliorate CVD in HGPS patients.

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Nuclear membrane ruptures underlie the vascular pathology in a mouse model of Hutchinson-Gilford progeria syndrome

Cited by 26 publications

References 54 publications

Mechanisms of A-Type Lamin Targeting to Nuclear Ruptures Are Disrupted in LMNA- and BANF1-Associated Progerias

Mechanisms of A-Type Lamin Targeting to Nuclear Ruptures Are Disrupted in LMNA- and BANF1-Associated Progerias

Current Methods and Pipelines for Image-Based Quantitation of Nuclear Shape and Nuclear Envelope Abnormalities

Progerin triggers a phenotypic switch in vascular smooth muscle cells that causes replication stress and an aging-associated secretory signature

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