A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model

Capell, Brian C.; Olive, Michelle; Erdos, Michael R.; Cao, Kan; Faddah, Dina A.; Tavarez, Urraca; Conneely, Karen N.; Qu, Xuan; San, Hong; Ganesh, Santhi K.; Chen, Xiaoyan; Avallone, Hedwig; Kolodgie, Frank D.; Virmani, Renu; Nabel, Elizabeth G.; Collins, Francis S.

doi:10.1073/pnas.0807840105

Cited by 186 publications

(165 citation statements)

References 32 publications

Supporting

Mentioning

154

Contrasting

Unclassified

Order By: Relevance

“…With increasing numbers of cell divisions, several phenotypes can be observed including nuclear blebbing, which is seen in primary fibroblasts from HGPS patients, along with a reduced growth rate and increased senescence in culture. 8,9 Of note, mutations in humans and mice that disrupt Zmpste24, resulting in permanent farnesylation of an otherwise normal lamin A, also give rise to phenotypes similar to HGPS, supporting the hypothesis that retention of the farnesylated C terminus leads to the cellular phenotype. 6,10,11 Therapeutic Strategies for HGPS Without treatment, HGPS is a uniformly fatal disorder.…”

Section: Hgpsmentioning

confidence: 78%

“…13,14 Furthermore FTIs improve phenotype and life span in mouse models of progeria. 9,15 It is thought that FTIs, by preventing farnesylation of progerin, reduce the accumulation of progerin at the nuclear rim, reducing the damaging effects of the mutant protein on the nucleus. 13 The outcome of an openlabel HGPS clinical trial of the FTI lonafarnib is awaited with great interest.…”

Section: Hgpsmentioning

confidence: 99%

“…The G608G mouse model of HGPS has a cardiovascular phenotype that shows improvement with FTI treatment. 9 Experiments are now underway with this mouse model of HGPS to see whether everolimus (an analog of rapamycin) is capable of preventing the cardiovascular disease phenotype.…”

Section: Rapamycin Promotes Clearance Of Progerinmentioning

confidence: 99%

See 2 more Smart Citations

Rapamycin activates autophagy in Hutchinson-Gilford progeria syndrome

Graziotto¹,

Cao²,

Collins³

et al. 2012

Autophagy

Self Cite

View full text Add to dashboard Cite

Section: Hgpsmentioning

confidence: 78%

Section: Hgpsmentioning

confidence: 99%

See 1 more Smart Citation

Rapamycin activates autophagy in Hutchinson-Gilford progeria syndrome

Graziotto¹,

Cao²,

Collins³

et al. 2012

Autophagy

Self Cite

View full text Add to dashboard Cite

“…S5A,B). Nuclear blebbing has been considered the hallmark phenotype in HGPS cells, resulting from the abnormal anchorage of progerin to the inner nuclear membrane (Capell et al ., 2005, 2008; Dechat et al ., 2009, 2010). To assay MB's effects on nuclear morphology, mock‐ and MB‐treated cells were immunostained with antilamin A/C and antiprogerin antibodies (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…4F–J). Previous literatures reported that releasing progerin from the nuclear membrane by farnesyltransferase inhibitor treatment partially rescued the gene expression and morphological defects in HGPS cells (Capell et al ., 2005, 2008; Capell & Collins, 2006; Gelb et al ., 2006; Cao et al ., 2007; Wang et al ., 2007; Marji et al ., 2010). Indeed, we find that not only the nuclear morphology but also the chromatin organization and gene expression are improved in the MB‐treated HGPS nucleus (Fig.…”

Section: Discussionmentioning

confidence: 99%

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

et al. 2015

Self Cite

View full text Add to dashboard Cite

SummaryHutchinson–Gilford progeria syndrome (HGPS), a fatal premature aging disease, is caused by a single‐nucleotide mutation in the LMNA gene. Previous reports have focused on nuclear phenotypes in HGPS cells, yet the potential contribution of the mitochondria, a key player in normal aging, remains unclear. Using high‐resolution microscopy analysis, we demonstrated a significantly increased fraction of swollen and fragmented mitochondria and a marked reduction in mitochondrial mobility in HGPS fibroblast cells. Notably, the expression of PGC‐1α, a central regulator of mitochondrial biogenesis, was inhibited by progerin. To rescue mitochondrial defects, we treated HGPS cells with a mitochondrial‐targeting antioxidant methylene blue (MB). Our analysis indicated that MB treatment not only alleviated the mitochondrial defects but also rescued the hallmark nuclear abnormalities in HGPS cells. Additional analysis suggested that MB treatment released progerin from the nuclear membrane, rescued perinuclear heterochromatin loss and corrected misregulated gene expression in HGPS cells. Together, these results demonstrate a role of mitochondrial dysfunction in developing the premature aging phenotypes in HGPS cells and suggest MB as a promising therapeutic approach for HGPS.

show abstract

Cellular Basis of Laminopathies

Cao

2012

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

The nuclear lamina is the main architectural component of a eukaryotic nucleus. More than an inert scaffold, the lamina is essential for maintaining proper nuclear organisation, epigenetic composition, transcriptional regulation and cell cycle progression. Mutations within lamin genes lead to a wide range of diseases known as laminopathies, among which the striking premature aging disease Hutchinson–Gilford progeria syndrome (HGPS) is the most well known. Studies regarding the cellular basis of laminopathies have advanced our knowledge of the nuclear lamina and yielded remarkable insights into the process of normal human aging. Understanding the molecular mechanisms responsible for disease manifestations has also led to the development of novel therapeutic strategies to address lamina‐related diseases. Ultimately, scientists and clinicians seek to provide treatment options to laminopathy patients to alleviate symptoms and perhaps to cure these diseases in the future. Key Concepts: Mutations in genes encoding lamin proteins lead to a wide range of diseases known as laminopathies. The nuclear lamina plays essential roles in maintaining nuclear architecture, chromatin organisation, cellular differentiation and gene expression. Studies of the molecular mechanisms underlying laminopathies have led to advances in the understanding of lamin structure and function. Progerin, the mutant form of lamin A expressed in Hutchinson–Gilford progeria syndrome, is also present in normal individuals, albeit at a low level. Recent advances have led to the development of noval therapeutic options for patients suffering from HGPS.

show abstract

A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model

Cited by 186 publications

References 32 publications

Rapamycin activates autophagy in Hutchinson-Gilford progeria syndrome

Rapamycin activates autophagy in Hutchinson-Gilford progeria syndrome

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

Cellular Basis of Laminopathies

Contact Info

Product

Resources

About