Blocking farnesylation of the prelamin A variant in Hutchinson-Gilford progeria syndrome alters the distribution of A-type lamins

Wang, Yuexia; Östlund, Cecilia; Choi, Jong‐Soo; Swayne, Theresa C.; Gundersen, Gregg G.; Worman, Howard J.

doi:10.4161/nucl.21675

Cited by 28 publications

(27 citation statements)

References 65 publications

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“…21 In further support of the idea that A-and B-type lamins form separate networks, blocking farnesylation of transfected progerin by CAAX motif mutation or FTI treatment leads to the redistribution of LA and LC away from the nuclear envelope, but does not disrupt the localization of LB1. 60 Further studies on the farnesylation of the lamins will be needed to determine the functional role or roles of this modification in lamin-dependent processes. 63×/1.4 oil objective.…”

Section: Methodsmentioning

confidence: 99%

Disruption of lamin B1 and lamin B2 processing and localization by farnesyltransferase inhibitors

Adam¹,

Butin‐Israeli²,

Cleland³

et al. 2013

Nucleus

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Section: Methodsmentioning

confidence: 99%

Disruption of lamin B1 and lamin B2 processing and localization by farnesyltransferase inhibitors

Adam¹,

Butin‐Israeli²,

Cleland³

et al. 2013

Nucleus

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“…137,138 Conversely, a premature aging phenotype in mice is attenuated using inhibitors of farnesylation of prelamin A. 139–143 …”

Section: Other Antiretroviral Side Effects: Aging and Pismentioning

confidence: 99%

Aging and HIV/AIDS: pathogenetic role of therapeutic side effects

Torres

Lewis

2014

Laboratory Investigation

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The intersection of aging and HIV/AIDS is a looming ‘epidemic within an epidemic.’ This paper reviews how HIV/AIDS and its therapy cause premature aging or contribute mechanistically to HIV-associated non-AIDS illnesses (HANA). Survival with HIV/AIDS has markedly improved by therapy combinations containing nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors, and protease inhibitors (PIs) called HAART (highly active anti-retroviral therapy). Because NRTIs and PIs together prevent or attenuate HIV-1 replication, and prolong life, the population of aging patients with HIV/AIDS increases accordingly. However, illnesses frequently associated with aging in the absence of HIV/AIDS appear to occur prematurely in HIV/AIDS patients. Theories that help to explain biological aging include oxidative stress (where mitochondrial oxidative injury exceeds antioxidant defense), chromosome telomere shortening with associated cellular senescence, and accumulation of lamin A precursors (a nuclear envelop protein). Each of these has the potential to be enhanced or caused by HIV/AIDS, antiretroviral therapy, or both. Antiretroviral therapy has been shown to enhance events seen in biological aging. Specifically, antiretroviral NRTIs cause mitochondrial dysfunction, oxidative stress, and mitochondrial DNA defects that resemble features of both HANA and aging. More recent clinical evidence points to telomere shortening caused by NRTI triphosphate-induced inhibition of telomerase, suggesting telomerase reverse transcriptase (TERT) inhibition as being a pathogenetic contributor to premature aging in HIV/AIDS. PIs may also have a role in premature aging in HIV/AIDS as they cause prelamin A accumulation. Overall, toxic side effects of HAART may both resemble and promote events of aging and are worthy of mechanistic studies.

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“…Materials and methods for protein extraction, electrophoresis, immunoblotting, immunofluorescence microscopy and FTI treatment of cells were as those described previously (Wang et al, 2012). Primary antibodies were rabbit anti-lamin A/C (H110, sc-20681, Santa Cruz) used at a dilution of 1:2000 for immunofluorescence microscopy or 1:6000 for immunoblotting, mouse anti-GAPDH (6C5, AM4300, Ambion) used at a dilution of 1:3000 and rat anti-prelamin-A [Lee et al, 2010; generously provided by Drs Loren Fong and Stephen G. Young, University of California, Los Angeles, CA] used at a dilution of 1:3000.…”

Section: Immunoblotting and Immunofluorescence Microscopymentioning

confidence: 99%

“…Cells were cultured in Chang medium D (Irvine Scientific) and showed no evidence of contamination. In some experiments, cells were treated with 2.5 µM FTI-277 (Sigma) dissolved in dimethyl sulfoxide (DMSO) or DMSO alone, as described previously (Wang et al, 2012).…”

Section: Cells and Cell Culturementioning

confidence: 99%

A mutation abolishing the ZMPSTE24 cleavage site in prelamin A causes a progeroid disorder

Wang

Lichter‐Konecki

Anyane‐Yeboa

et al. 2016

Journal of Cell Science

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In 1994 in the Journal of Cell Science, Hennekes and Nigg reported that changing valine to arginine at the endoproteolytic cleavage site in chicken prelamin A abolished its conversion to lamin A. The consequences of this mutation in an organism have remained unknown. We now report that the corresponding mutation in a human subject leads to accumulation of prelamin A and causes a progeroid disorder. Next generation sequencing of the subject and her parents' exomes identified a de novo mutation in the lamin A/C gene that resulted in a leucine to arginine amino acid substitution at residue 647 in prelamin A. The subject's fibroblasts accumulated prelamin A, a farnesylated protein, which led to an increased percentage of cultured cells with morphologically abnormal nuclei. Treatment with a protein farnesyltransferase inhibitor improved abnormal nuclear morphology. This case demonstrates that accumulation of prelamin A, independent of loss of function of ZMPSTE24 metallopeptidase that catalyzes it processing, can cause a progeroid disorder and suggests a precision medicine approach to therapy based on results of a cell biological assay.

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Blocking farnesylation of the prelamin A variant in Hutchinson-Gilford progeria syndrome alters the distribution of A-type lamins

Cited by 28 publications

References 65 publications

Disruption of lamin B1 and lamin B2 processing and localization by farnesyltransferase inhibitors

Disruption of lamin B1 and lamin B2 processing and localization by farnesyltransferase inhibitors

Aging and HIV/AIDS: pathogenetic role of therapeutic side effects

A mutation abolishing the ZMPSTE24 cleavage site in prelamin A causes a progeroid disorder

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