LIVIVO - Search results -

Search results

Result 1 - 10 of total 12

Search options

Article ; Online: Subcellular Force Imbalance in Actin Bundles Induces Nuclear Repositioning and Durotaxis.

Jun, Myeongjun / Lee, Yin Loon / Zhou, Tianxun / Maric, Martina / Burke, Brian / Park, Sungsu / Low, Boon Chuan / Chiam, Keng-Hwee

ACS applied materials & interfaces

2023 Volume 15, Issue 37, Page(s) 43387–43402

Abstract: Durotaxis is a phenomenon in which cells migrate toward substrates of increasing stiffness. However, how cells assimilate substrate stiffness as a directional cue remains poorly understood. In this study, we experimentally show that mouse embryonic ... ...

Abstract	Durotaxis is a phenomenon in which cells migrate toward substrates of increasing stiffness. However, how cells assimilate substrate stiffness as a directional cue remains poorly understood. In this study, we experimentally show that mouse embryonic fibroblasts can discriminate between different substrate stiffnesses and develop higher traction forces at regions of the cell adhering to the stiffer pillars. In this way, the cells generate a force imbalance between adhesion sites. It is this traction force imbalance that drives durotaxis by providing directionality for cell migration. Significantly, we found that traction forces are transmitted via LINC complexes to the cell nucleus, which serves to maintain the global force imbalance. In this way, LINC complexes play an essential role in anterograde nuclear movement and durotaxis. This conclusion is supported by the fact that LINC complex-deficient cells are incapable of durotaxis and instead migrate randomly on substrates featuring a stiffness gradient.
MeSH term(s)	Animals ; Mice ; Actins ; Fibroblasts ; Cell Movement ; Biological Transport ; Cell Nucleus
Chemical Substances	Actins
Language	English
Publishing date	2023-09-06
Publishing country	United States
Document type	Journal Article
ISSN	1944-8252
ISSN (online)	1944-8252
DOI	10.1021/acsami.3c07546
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Article ; Online: LINC complexes and nuclear positioning.

Lee, Yin Loon / Burke, Brian

Seminars in cell & developmental biology

2017 Volume 82, Page(s) 67–76

Abstract: One of the characteristics of eukaryotic cells is their structural plasticity associated with the ability to carry out a broad range of complex functions, both autonomously and as components of tissues and organs. Major cellular rearrangements can be ... ...

Abstract	One of the characteristics of eukaryotic cells is their structural plasticity associated with the ability to carry out a broad range of complex functions, both autonomously and as components of tissues and organs. Major cellular rearrangements can be observed in various systems from meiosis in fission yeast, through dermal differentiation in nematodes, to muscle and neuronal development in vertebrates. Each of these processes involves oftentimes dramatic relocation of the nucleus within the cell. During the last decade it has become apparent that the nuclear periphery represents a nexus of cytoskeletal interactions that are involved not only in nuclear movement but also in the distribution and dissemination of mechanical forces throughout the cell. Nucleocytoskeletal coupling is mediated in large part by SUN- and KASH-domain proteins of the nuclear membranes, that together assemble to form LINC (Linker of the Nucleoskeleton and Cytoskeleton) complexes. In this review we will describe how the LINC complex repertoire contributes to nuclear positioning and chromosome dynamics in a variety of cellular contexts.
MeSH term(s)	Animals ; Biological Transport ; Cell Nucleus/metabolism ; Humans ; RNA, Long Noncoding/metabolism
Chemical Substances	RNA, Long Noncoding
Language	English
Publishing date	2017-11-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1312473-0
ISSN	1096-3634 ; 1084-9521
ISSN (online)	1096-3634
ISSN	1084-9521
DOI	10.1016/j.semcdb.2017.11.008
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 2918: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾

Article ; Online: Systematic in vivo candidate evaluation uncovers therapeutic targets for LMNA dilated cardiomyopathy and risk of Lamin A toxicity.

Tan, Chia Yee / Chan, Pui Shi / Tan, Hansen / Tan, Sung Wei / Lee, Chang Jie Mick / Wang, Jiong-Wei / Ye, Shu / Werner, Hendrikje / Loh, Ying Jie / Lee, Yin Loon / Ackers-Johnson, Matthew / Foo, Roger S Y / Jiang, Jianming

Journal of translational medicine

2023 Volume 21, Issue 1, Page(s) 690

Abstract: Background: Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease which ultimately results in heart failure (HF). Decades of research on DCM have revealed diverse aetiologies. Among them, familial DCM is the major form of DCM, with ... ...

Abstract	Background: Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease which ultimately results in heart failure (HF). Decades of research on DCM have revealed diverse aetiologies. Among them, familial DCM is the major form of DCM, with pathogenic variants in LMNA being the second most common form of autosomal dominant DCM. LMNA DCM is a multifactorial and complex disease with no specific treatment thus far. Many studies have demonstrated that perturbing candidates related to various dysregulated pathways ameliorate LMNA DCM. However, it is unknown whether these candidates could serve as potential therapeutic targets especially in long term efficacy. Methods: We evaluated 14 potential candidates including Lmna gene products (Lamin A and Lamin C), key signaling pathways (Tgfβ/Smad, mTor and Fgf/Mapk), calcium handling, proliferation regulators and modifiers of LINC complex function in a cardiac specific Lmna DCM model. Positive candidates for improved cardiac function were further assessed by survival analysis. Suppressive roles and mechanisms of these candidates in ameliorating Lmna DCM were dissected by comparing marker gene expression, Tgfβ signaling pathway activation, fibrosis, inflammation, proliferation and DNA damage. Furthermore, transcriptome profiling compared the differences between Lamin A and Lamin C treatment. Results: Cardiac function was restored by several positive candidates (Smad3, Yy1, Bmp7, Ctgf, aYAP1, Sun1, Lamin A, and Lamin C), which significantly correlated with suppression of HF/fibrosis marker expression and cardiac fibrosis in Lmna DCM. Lamin C or Sun1 shRNA administration achieved consistent, prolonged survival which highly correlated with reduced heart inflammation and DNA damage. Importantly, Lamin A treatment improved but could not reproduce long term survival, and Lamin A administration to healthy hearts itself induced DCM. Mechanistically, we identified this lapse as caused by a dose-dependent toxicity of Lamin A, which was independent from its maturation. Conclusions: In vivo candidate evaluation revealed that supplementation of Lamin C or knockdown of Sun1 significantly suppressed Lmna DCM and achieve prolonged survival. Conversely, Lamin A supplementation did not rescue long term survival and may impart detrimental cardiotoxicity risk. This study highlights a potential of advancing Lamin C and Sun1 as therapeutic targets for the treatment of LMNA DCM.
MeSH term(s)	Humans ; Cardiomyopathy, Dilated/genetics ; Cardiomyopathy, Dilated/pathology ; Lamin Type A/genetics ; Lamin Type A/metabolism ; Cardiomyopathies ; Fibrosis ; Inflammation/complications ; Transforming Growth Factor beta ; Mutation
Chemical Substances	Lamin Type A ; Transforming Growth Factor beta ; LMNA protein, human
Language	English
Publishing date	2023-10-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2118570-0
ISSN	1479-5876 ; 1479-5876
ISSN (online)	1479-5876
ISSN	1479-5876
DOI	10.1186/s12967-023-04542-4
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Nesprin-1 LINC complexes recruit microtubule cytoskeleton proteins and drive pathology in Lmna-mutant striated muscle.

Leong, Ei Leen / Khaing, Nyein Thet / Cadot, Bruno / Hong, Wei Liang / Kozlov, Serguei / Werner, Hendrikje / Wong, Esther Sook Miin / Stewart, Colin L / Burke, Brian / Lee, Yin Loon

Human molecular genetics

2022 Volume 32, Issue 2, Page(s) 177–191

Abstract: Mutations in LMNA, the gene encoding A-type lamins, cause laminopathies-diseases of striated muscle and other tissues. The aetiology of laminopathies has been attributed to perturbation of chromatin organization or structural weakening of the nuclear ... ...

Abstract	Mutations in LMNA, the gene encoding A-type lamins, cause laminopathies-diseases of striated muscle and other tissues. The aetiology of laminopathies has been attributed to perturbation of chromatin organization or structural weakening of the nuclear envelope (NE) such that the nucleus becomes more prone to mechanical damage. The latter model requires a conduit for force transmission to the nucleus. NE-associated Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes are one such pathway. Using clustered regularly interspaced short palindromic repeats to disrupt the Nesprin-1 KASH (Klarsicht, ANC-1, Syne Homology) domain, we identified this LINC complex protein as the predominant NE anchor for microtubule cytoskeleton components, including nucleation activities and motor complexes, in mouse cardiomyocytes. Loss of Nesprin-1 LINC complexes resulted in loss of microtubule cytoskeleton proteins at the nucleus and changes in nuclear morphology and positioning in striated muscle cells, but with no overt physiological defects. Disrupting the KASH domain of Nesprin-1 suppresses Lmna-linked cardiac pathology, likely by reducing microtubule cytoskeleton activities at the nucleus. Nesprin-1 LINC complexes thus represent a potential therapeutic target for striated muscle laminopathies.
MeSH term(s)	Animals ; Mice ; Microtubule Proteins/metabolism ; Nuclear Proteins/metabolism ; Membrane Proteins/genetics ; Cytoskeleton/genetics ; Cytoskeleton/metabolism ; Nuclear Matrix/genetics ; Microtubules/metabolism ; Nuclear Envelope/genetics ; Nuclear Envelope/metabolism ; Intermediate Filament Proteins/metabolism ; Muscle, Striated/metabolism ; Laminopathies/metabolism
Chemical Substances	Microtubule Proteins ; Nuclear Proteins ; Membrane Proteins ; Intermediate Filament Proteins
Language	English
Publishing date	2022-08-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddac179
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 3469: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article: Observing planar cell polarity in multiciliated mouse airway epithelial cells.

Vladar, Eszter K / Lee, Yin Loon / Stearns, Tim / Axelrod, Jeffrey D

Methods in cell biology

2015 Volume 127, Page(s) 37–54

Abstract: The concerted movement of cilia propels inhaled contaminants out of the lungs, safeguarding the respiratory system from toxins, pathogens, pollutants, and allergens. Motile cilia on the multiciliated cells (MCCs) of the airway epithelium are physically ... ...

Abstract	The concerted movement of cilia propels inhaled contaminants out of the lungs, safeguarding the respiratory system from toxins, pathogens, pollutants, and allergens. Motile cilia on the multiciliated cells (MCCs) of the airway epithelium are physically oriented along the tissue axis for directional motility, which depends on the planar cell polarity (PCP) signaling pathway. The MCCs of the mouse respiratory epithelium have emerged as an important model for the study of motile ciliogenesis and the PCP signaling mechanism. Unlike other motile ciliated or planar polarized tissues, airway epithelial cells are relatively easily accessible and primary cultures faithfully model many of the essential features of the in vivo tissue. There is growing interest in understanding how cells acquire and polarize motile cilia due to the impact of mucociliary clearance on respiratory health. Here, we present methods for observing and quantifying the planar polarized orientation of motile cilia both in vivo and in primary culture airway epithelial cells. We describe how to acquire and evaluate electron and light microscopy images of ciliary ultrastructural features that reveal planar polarized orientation. Furthermore, we describe the immunofluorescence localization of PCP pathway components as a simple readout for airway epithelial planar polarization and ciliary orientation. These methods can be adapted to observe ciliary orientation in other multi- and monociliated cells and to detect PCP pathway activity in any tissue or cell type.
MeSH term(s)	Animals ; Carrier Proteins/analysis ; Cell Polarity/physiology ; Cilia/physiology ; Epithelial Cells/cytology ; Epithelial Cells/physiology ; Fluorescent Antibody Technique/methods ; Frizzled Receptors/analysis ; Lung/cytology ; Lung/physiology ; Membrane Proteins/analysis ; Mice ; Microscopy, Electron, Transmission/methods ; Primary Cell Culture/methods ; Respiratory Mucosa/cytology ; Respiratory Mucosa/physiology ; Signal Transduction ; Staining and Labeling/methods ; Tissue Fixation/methods ; Trachea/cytology ; Trachea/surgery
Chemical Substances	Carrier Proteins ; Frizzled Receptors ; Fzd6 protein, mouse ; Membrane Proteins ; Vangl1 protein, mouse
Language	English
Publishing date	2015-03-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	0091-679X
ISSN	0091-679X
DOI	10.1016/bs.mcb.2015.01.016
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article: STED Microscopy with Optimized Labeling Density Reveals 9-Fold Arrangement of a Centriole Protein

Lau, Lana / Lee, Yin Loon / Sahl, Steffen J / Stearns, Tim / Moerner, W.E

Biophysical journal. 2012 June 20, v. 102, no. 12

2012

Abstract: Super-resolution fluorescence microscopy can achieve resolution beyond the optical diffraction limit, partially closing the gap between conventional optical imaging and electron microscopy for elucidation of subcellular architecture. The centriole, a key ...

Abstract	Super-resolution fluorescence microscopy can achieve resolution beyond the optical diffraction limit, partially closing the gap between conventional optical imaging and electron microscopy for elucidation of subcellular architecture. The centriole, a key component of the cellular control and division machinery, is 250 nm in diameter, a spatial scale where super-resolution methods such as stimulated emission depletion (STED) microscopy can provide previously unobtainable detail. We use STED with a resolution of 60 nm to demonstrate that the centriole distal appendage protein Cep164 localizes in nine clusters spaced around a ring of ∼300 nm in diameter, and quantify the influence of the labeling density in STED immunofluorescence microscopy. We find that the labeling density dramatically influences the observed number, size, and brightness of labeled Cep164 clusters, and estimate the average number of secondary antibody labels per cluster. The arrangements are morphologically similar in centrioles of both proliferating cells and differentiated multiciliated cells, suggesting a relationship of this structure to function. Our STED measurements in single centrioles are consistent with results obtained by electron microscopy, which involve ensemble averaging or very different sample preparation conditions, suggesting that we have arrived at a direct measurement of a centriole protein by careful optimization of the labeling density.
Keywords	centrioles ; electron microscopy ; fluorescence microscopy ; image analysis
Language	English
Dates of publication	2012-0620
Size	p. 2926-2935.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2012.05.015
Database	NAL-Catalogue (AGRICOLA)

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Bonn / Germany

Z 4' 66/63: Show issues

Order via subito

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Details ▾

Article: STED Super-resolution Microscopy in

Lau, Lana / Lee, Yin Loon / Matis, Maja / Axelrod, Jeff / Stearns, Tim / Moerner, W E

Proceedings of SPIE--the International Society for Optical Engineering

2013 Volume 7910

Abstract: Far-field super-resolution microscopy is a rapidly emerging method that is opening up opportunities for biological imaging beyond the optical diffraction limit. We have implemented a Stimulated Emission Depletion (STED) microscope to image single dye, ... ...

Abstract	Far-field super-resolution microscopy is a rapidly emerging method that is opening up opportunities for biological imaging beyond the optical diffraction limit. We have implemented a Stimulated Emission Depletion (STED) microscope to image single dye, cell, and tissue samples with 50-80 nm resolution. First, we compare the STED performance imaging single molecules of several common dyes and report a novel STED dye. Then we apply STED to image planar cell polarity protein complexes in intact fixed
Language	English
Publishing date	2013-02-27
Publishing country	United States
Document type	Journal Article
ISSN	0277-786X
ISSN	0277-786X
DOI	10.1117/12.881221
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Article ; Online: STED microscopy with optimized labeling density reveals 9-fold arrangement of a centriole protein.

Lau, Lana / Lee, Yin Loon / Sahl, Steffen J / Stearns, Tim / Moerner, W E

Biophysical journal

2012 Volume 102, Issue 12, Page(s) 2926–2935

Abstract	Super-resolution fluorescence microscopy can achieve resolution beyond the optical diffraction limit, partially closing the gap between conventional optical imaging and electron microscopy for elucidation of subcellular architecture. The centriole, a key component of the cellular control and division machinery, is 250 nm in diameter, a spatial scale where super-resolution methods such as stimulated emission depletion (STED) microscopy can provide previously unobtainable detail. We use STED with a resolution of 60 nm to demonstrate that the centriole distal appendage protein Cep164 localizes in nine clusters spaced around a ring of ∼300 nm in diameter, and quantify the influence of the labeling density in STED immunofluorescence microscopy. We find that the labeling density dramatically influences the observed number, size, and brightness of labeled Cep164 clusters, and estimate the average number of secondary antibody labels per cluster. The arrangements are morphologically similar in centrioles of both proliferating cells and differentiated multiciliated cells, suggesting a relationship of this structure to function. Our STED measurements in single centrioles are consistent with results obtained by electron microscopy, which involve ensemble averaging or very different sample preparation conditions, suggesting that we have arrived at a direct measurement of a centriole protein by careful optimization of the labeling density.
MeSH term(s)	Animals ; Antibodies/chemistry ; Antibodies/metabolism ; Cell Line ; Cell Proliferation ; Centrioles ; Epithelial Cells/cytology ; Mice ; Microscopy/methods ; Microtubule Proteins/chemistry ; Microtubule Proteins/metabolism ; Staining and Labeling
Chemical Substances	Antibodies ; Microtubule Proteins
Language	English
Publishing date	2012-06-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2012.05.015
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 235: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 2: Show issues

Order via subito

Details ▾

Article ; Online: Nesprin-1α-Dependent Microtubule Nucleation from the Nuclear Envelope via Akap450 Is Necessary for Nuclear Positioning in Muscle Cells.

Gimpel, Petra / Lee, Yin Loon / Sobota, Radoslaw M / Calvi, Alessandra / Koullourou, Victoria / Patel, Rutti / Mamchaoui, Kamel / Nédélec, François / Shackleton, Sue / Schmoranzer, Jan / Burke, Brian / Cadot, Bruno / Gomes, Edgar R

Current biology : CB

2017 Volume 27, Issue 19, Page(s) 2999–3009.e9

Abstract: The nucleus is the main microtubule-organizing center (MTOC) in muscle cells due to the accumulation of centrosomal proteins and microtubule (MT) nucleation activity at the nuclear envelope (NE) [1-4]. The relocalization of centrosomal proteins, ... ...

Abstract	The nucleus is the main microtubule-organizing center (MTOC) in muscle cells due to the accumulation of centrosomal proteins and microtubule (MT) nucleation activity at the nuclear envelope (NE) [1-4]. The relocalization of centrosomal proteins, including Pericentrin, Pcm1, and γ-tubulin, depends on Nesprin-1, an outer nuclear membrane (ONM) protein that connects the nucleus to the cytoskeleton via its N-terminal region [5-7]. Nesprins are also involved in the recruitment of kinesin to the NE and play a role in nuclear positioning in skeletal muscle cells [8-12]. However, a function for MT nucleation from the NE in nuclear positioning has not been established. Using the proximity-dependent biotin identification (BioID) method [13, 14], we found several centrosomal proteins, including Akap450, Pcm1, and Pericentrin, whose association with Nesprin-1α is increased in differentiated myotubes. We show that Nesprin-1α recruits Akap450 to the NE independently of kinesin and that Akap450, but not other centrosomal proteins, is required for MT nucleation from the NE. Furthermore, we demonstrate that this mechanism is disrupted in congenital muscular dystrophy patient myotubes carrying a nonsense mutation within the SYNE1 gene (23560 G>T) encoding Nesprin-1 [15, 16]. Finally, using computer simulation and cell culture systems, we provide evidence for a role of MT nucleation from the NE on nuclear spreading in myotubes. Our data thus reveal a novel function for Nesprin-1α/Nesprin-1 in nuclear positioning through recruitment of Akap450-mediated MT nucleation activity to the NE.
MeSH term(s)	A Kinase Anchor Proteins/genetics ; A Kinase Anchor Proteins/metabolism ; Animals ; Cell Line ; Cytoskeletal Proteins ; Female ; HeLa Cells ; Humans ; Mice ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Microtubules/metabolism ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Nuclear Envelope/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Rats
Chemical Substances	A Kinase Anchor Proteins ; Akap9 protein, mouse ; Cytoskeletal Proteins ; Microtubule-Associated Proteins ; Nerve Tissue Proteins ; Nuclear Proteins ; Syne1 protein, mouse
Language	English
Publishing date	2017-09-28
Publishing country	England
Document type	Journal Article
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2017.08.031
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 3208: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾

Article ; Online: Disrupting the LINC complex by AAV mediated gene transduction prevents progression of Lamin induced cardiomyopathy.

Chai, Ruth Jinfen / Werner, Hendrikje / Li, Peter Yiqing / Lee, Yin Loon / Nyein, Khaing Thet / Solovei, Irina / Luu, Tuan Danh Anh / Sharma, Bhavya / Navasankari, Raju / Maric, Martina / Sim, Lois Yu En / Loh, Ying Jie / Aliwarga, Edita / Cheong, Jason Wen Long / Chojnowski, Alexandre / Autio, Matias Ilmari / Haiyang, Yu / Boon Tan, Kenneth Kian / Keng, Choong Tat /

Ng, Shi Ling / Chew, Wei Leong / Ferenczi, Michael / Burke, Brian / Foo, Roger Sik Yin / Stewart, Colin L

Nature communications

2021 Volume 12, Issue 1, Page(s) 4722

Abstract: Mutations in the LaminA gene are a common cause of monogenic dilated cardiomyopathy. Here we show that mice with a cardiomyocyte-specific Lmna deletion develop cardiac failure and die within 3-4 weeks after inducing the mutation. When the same Lmna ... ...

Abstract	Mutations in the LaminA gene are a common cause of monogenic dilated cardiomyopathy. Here we show that mice with a cardiomyocyte-specific Lmna deletion develop cardiac failure and die within 3-4 weeks after inducing the mutation. When the same Lmna mutations are induced in mice genetically deficient in the LINC complex protein SUN1, life is extended to more than one year. Disruption of SUN1's function is also accomplished by transducing and expressing a dominant-negative SUN1 miniprotein in Lmna deficient cardiomyocytes, using the cardiotrophic Adeno Associated Viral Vector 9. The SUN1 miniprotein disrupts binding between the endogenous LINC complex SUN and KASH domains, displacing the cardiomyocyte KASH complexes from the nuclear periphery, resulting in at least a fivefold extension in lifespan. Cardiomyocyte-specific expression of the SUN1 miniprotein prevents cardiomyopathy progression, potentially avoiding the necessity of developing a specific therapeutic tailored to treating each different LMNA cardiomyopathy-inducing mutation of which there are more than 450.
MeSH term(s)	Animals ; Cardiomyopathy, Dilated/genetics ; Cardiomyopathy, Dilated/pathology ; Cardiomyopathy, Dilated/physiopathology ; Dependovirus/genetics ; Female ; Humans ; Lamin Type A/deficiency ; Lamin Type A/genetics ; Lamin Type A/metabolism ; Male ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Knockout ; Microtubule-Associated Proteins/deficiency ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Transduction, Genetic
Chemical Substances	Lamin Type A ; Lmna protein, mouse ; Microtubule-Associated Proteins ; SUN1 protein, mouse
Language	English
Publishing date	2021-08-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-24849-4
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

To top

More links

Kategorien

Order via subito

Inter-library loan at ZB MED

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Bonn / Germany

Order via subito

Inter-library loan at ZB MED

More links

Kategorien

Order via subito

Inter-library loan at ZB MED

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito