Progeria: A Paradigm for Translational Medicine

Gordon, Leslie B.; Rothman, Frank G.; López-Otı́n, Carlos; Misteli, Tom

doi:10.1016/j.cell.2013.12.028

Cited by 238 publications

(274 citation statements)

References 72 publications

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“…Some HGPS and aging hallmarks are replicated in Zmpste24 ‐deficient mice due to loss of lamin A maturation (Bergo et al, 2002; Burtner, & Kennedy, 2010; Gordon, Rothman, Lopez‐Otin, & Misteli, 2014; Ibrahim et al, 2013). Our results using Pla2r1 and Zmpste24 double‐knockout mice support a functional role for PLA2R1 in controlling cellular senescence and some aging hallmarks.…”

Section: Discussionmentioning

confidence: 99%

Targeting the phospholipase A2 receptor ameliorates premature aging phenotypes

et al. 2018

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Hutchinson–Gilford progeria syndrome (HGPS) is a lethal premature aging that recapitulates many normal aging characteristics. This disorder is caused by mutation in the LMNA gene leading to the production of progerin which induces misshapen nuclei, cellular senescence, and aging. We previously showed that the phospholipase A2 receptor (PLA2R1) promotes senescence induced by replicative, oxidative, and oncogenic stress but its role during progerin‐induced senescence and in progeria is currently unknown. Here, we show that knockdown of PLA2R1 prevented senescence induced by progerin expression in human fibroblasts and markedly delayed senescence of HGPS patient‐derived fibroblasts. Whole‐body knockout of Pla2r1 in a mouse model of progeria decreased some premature aging phenotypes, such as rib fracture and decreased bone content, together with decreased senescence marker. Progerin‐expressing human fibroblasts exhibited a high frequency of misshapen nuclei and increased farnesyl diphosphate synthase (FDPS) expression compared to controls; knockdown of PLA2R1 reduced the frequency of misshapen nuclei and normalized FDPS expression. Pamidronate, a FDPS inhibitor, also reduced senescence and misshapen nuclei. Downstream of PLA2R1, we found that p53 mediated the progerin‐induced increase in FDPS expression and in misshapen nuclei. These results suggest that PLA2R1 mediates key premature aging phenotypes through a p53/FDPS pathway and might be a new therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Targeting the phospholipase A2 receptor ameliorates premature aging phenotypes

et al. 2018

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“…ICMT inhibitors may also have utility in treating progeria, the pathology of which is attributed to the accumulation of a prenylated and methylated form of prelamin A at the nuclear envelope 3,24 . The structure would aid inhibitor development efforts.…”

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confidence: 99%

Atomic structure of the eukaryotic intramembrane RAS methyltransferase ICMT

Diver

Pedi

Koide

et al. 2018

Nature

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The maturation of Ras GTPases, and ~200 other cellular CaaX proteins, involves three enzymatic steps: addition of a farnesyl or geranylgeranyl prenyl lipid to the cysteine (C) in the C-terminal CaaX motif, proteolytic cleavage of the aaX residues, and methylation of the exposed prenylcysteine residue at its terminal carboxylate1. This final step is catalyzed by isoprenylcysteine carboxyl methyltransferase (ICMT), a eukaryotic-specific integral membrane enzyme of the endoplasmic reticulum (ER)2. ICMT is the only cellular enzyme known to methylate prenylcysteine substrates; methylation is important for their biological functions, including the membrane localisations and subsequent activities of Ras1, prelamin A3, and Rab4. ICMT inhibition has potential for combating progeria3 and cancer5–8. Here we present an X-ray structure of ICMT, at 2.3 Å resolution, in complex with its cofactor, an ordered lipid molecule and a monobody inhibitor. The active site spans cytosolic and membrane-exposed regions, indicating distinct entry routes for its cytosolic methyl donor, S-adenosyl-L-methionine (AdoMet), and for prenylcysteine substrates, which are associated with the ER membrane. The structure suggests how ICMT overcomes the topographical challenge and unfavourable energetics of bringing two reactants that have different cellular localisations together in a membrane environment – a relatively uncharacterized, but defining feature of many integral membrane enzymes.

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“…Several lines of evidence strongly support the view that this results in a toxic gain of function because the uncleaved protein is constitutively fernesylated, and this may explain the specific set of signs and symptoms that characterize HGPS. 12 The genotype/phenotype correlation for most other laminopathy-related variants is very weak and multiple allelic laminopathies are known to co-exist within the same family. 13,14 The capacity of some LMNA variants to cause autosomal dominant versus recessive laminopathies is a phenomenon not yet completely understood.…”

Section: Resultsmentioning

confidence: 99%

Distal acroosteolysis, poikiloderma and joint stiffness: a novel laminopathy?

et al. 2016

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LMNA encodes lamin A and lamin C, two major components of the nuclear lamina, and its pathogenic variants lead to a dozen distinct clinical entities collectively known as laminopathies. Most LMNA-related laminopathies are autosomal dominant but four are autosomal recessive; furthermore, some of the dominant variants have been associated with distinct phenotypes when inherited recessively, further complicating the ability to correlate genotype with phenotype. We report a consanguineous family in which the index presented with an apparently unique constellation of poikiloderma, joint motion restriction and distal acroosteolysis but lacks features of muscle weakness, lipodystrophy, or cardiac or craniofacial involvement. Molecular analysis revealed the presence of a novel homozygous LMNA missense variant (NM_170707.3:c.1774G4A; p.(Gly592Arg)) within an area of autozygome that is not shared by his unaffected siblings. The proposed causal link is further supported by in silico analysis of this variant. Our case suggests an expansion of LMNA allelic disorders to include distal acroosteolysis, poikiloderma and joint stiffness (DAPJ).

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Progeria: A Paradigm for Translational Medicine

Abstract: Rare diseases are powerful windows into biological processes and can serve as models for the development of therapeutic strategies. The progress made on the premature aging disorder Progeria is a shining example of the impact that studies of rare diseases can have.

Cited by 238 publications

References 72 publications

Targeting the phospholipase A2 receptor ameliorates premature aging phenotypes

Targeting the phospholipase A2 receptor ameliorates premature aging phenotypes

Atomic structure of the eukaryotic intramembrane RAS methyltransferase ICMT

Distal acroosteolysis, poikiloderma and joint stiffness: a novel laminopathy?

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