Rescue of heterochromatin organization in Hutchinson-Gilford progeria by drug treatment

Columbaro, Marta; Capanni, Cristina; Mattioli, Elisabetta; Novelli, Giuseppe; Parnaik, Veena K.; Squarzoni, Stefano; Maraldi, Nadir M.; Lattanzi, Giovanna

doi:10.1007/s00018-005-5318-6

Cited by 138 publications

(152 citation statements)

References 29 publications

Supporting

Mentioning

142

Contrasting

Order By: Relevance

“…It has been demonstrated that HGPS fibroblasts start acquiring a senescent phenotype at late passages (Columbaro et al, 2005; Goldman et al, 2004; Meaburn et al, 2007). We hypothesized that an altered response to stress stimuli could be a major determinant of cellular aging in those cells.…”

Section: Resultsmentioning

confidence: 99%

“…A number of epigenetic drugs, including TSA (Columbaro et al, 2005), MS275, and other small molecules targeting class I histone deacetylases, warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Anti‐lamin A/C and anti‐prelamin A antibodies used in this study have been previously characterized in control and HGPS cells (Cenni et al, 2014; Columbaro et al, 2005; Lattanzi et al, 2014). The class I HDAC inhibitor MS‐275 (entinostat) was applied 5 µM for 18 hr to fibroblasts cultures.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Mattioli¹,

Andrenacci²,

Garofalo

et al. 2018

Aging Cell

View full text Add to dashboard Cite

Defects in stress response are main determinants of cellular senescence and organism aging. In fibroblasts from patients affected by Hutchinson–Gilford progeria, a severe LMNA‐linked syndrome associated with bone resorption, cardiovascular disorders, and premature aging, we found altered modulation of CDKN1A, encoding p21, upon oxidative stress induction, and accumulation of senescence markers during stress recovery. In this context, we unraveled a dynamic interaction of lamin A/C with HDAC2, an histone deacetylase that regulates CDKN1A expression. In control skin fibroblasts, lamin A/C is part of a protein complex including HDAC2 and its histone substrates; protein interaction is reduced at the onset of DNA damage response and recovered after completion of DNA repair. This interplay parallels modulation of p21 expression and global histone acetylation, and it is disrupted by LMNAmutations leading to progeroid phenotypes. In fact, HGPS cells show impaired lamin A/C‐HDAC2 interplay and accumulation of p21 upon stress recovery. Collectively, these results link altered physical interaction between lamin A/C and HDAC2 to cellular and organism aging. The lamin A/C‐HDAC2 complex may be a novel therapeutic target to slow down progression of progeria symptoms.

show abstract

Section: Resultsmentioning

confidence: 99%

“…A number of epigenetic drugs, including TSA (Columbaro et al, 2005), MS275, and other small molecules targeting class I histone deacetylases, warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Mattioli¹,

Andrenacci²,

Garofalo

et al. 2018

Aging Cell

View full text Add to dashboard Cite

show abstract

“…An increased ratio of progerin to mature lamin A was also determined in a fibroblast cell line from a 9-year-old HGPS patient, when compared with fibroblasts of younger HGPS patients. 25 Related to the increased progerin to lamin A ratio, Columbaro et al 25 assumed a worsening with patient age. We suggest that an increase of the ratio of progerin to mature lamin A increases the severity of the clinical phenotype explaining the severe phenotype of patient N directly after birth.…”

Section: Discussionmentioning

confidence: 99%

Neonatal progeria: increased ratio of progerin to lamin A leads to progeria of the newborn

et al. 2012

View full text Add to dashboard Cite

Hutchinson-Gilford progeria syndrome (HGPS) is an important model disease for premature ageing. Affected children appear healthy at birth, but develop the first symptoms during their first year of life. They die at an average age of 13 years, mostly because of myocardial infarction or stroke. Classical progeria is caused by the heterozygous point mutation c.1824C4T in the LMNA gene, which activates a cryptic splice site. The affected protein cannot be processed correctly to mature lamin A, but is modified into a farnesylated protein truncated by 50 amino acids (progerin). Three more variations in LMNA result in the same mutant protein, but different grades of disease severity. We describe a patient with the heterozygous LMNA mutation c.1821G4A, leading to neonatal progeria with death in the first year of life. Intracellular lamin A was downregulated in the patient's fibroblasts and the ratio of progerin to lamin A was increased when compared with HGPS. It is suggestive that the ratio of farnesylated protein to mature lamin A determines the disease severity in progeria.

show abstract

“…This deletion interferes with posttranslational processing by removing a key protease cleavage site, leading to permanent farnesylation and aberrant anchorage of the mutant lamin A, termed progerin, to the nuclear membrane (Eriksson et al ., 2003; Capell & Collins, 2006). The abnormal presence of progerin disrupts the integrity of the nucleoskeleton, causing high levels of nuclear abnormalities including nuclear blebbing, altered chromatin organization, transcriptional changes, and aberrant mitosis (Goldman et al ., 2002, 2004; Columbaro et al ., 2005; Liu et al ., 2005; Shumaker et al ., 2006; Cao et al ., 2007; Dechat et al ., 2007, 2008; McCord et al ., 2013; Stancheva & Schirmer, 2014). …”

Section: Introductionmentioning

confidence: 99%

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

et al. 2015

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

Rescue of heterochromatin organization in Hutchinson-Gilford progeria by drug treatment

Cited by 138 publications

References 29 publications

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Neonatal progeria: increased ratio of progerin to lamin A leads to progeria of the newborn

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

Contact Info

Product

Resources

About