Alteration of splice site selection in the LMNA gene and inhibition of progerin production via AMPK activation

Finley, Jahahreeh

doi:10.1016/j.mehy.2014.08.016

Cited by 12 publications

(8 citation statements)

References 132 publications

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“…In our study, resveratrol treatment began at postnatal week 3, which combined with the different treatment duration and the type of transgenic animal model could account for the different findings. In addition, we showed that resveratrol treatment did not affect the levels of transgenic human lamin A, progerin, or their relative expression in bone, suggesting unaffected splicing, contradicting a recently published theory that resveratrol via AMPK activation would decrease progerin production (39). It has previously been shown that lamin A directly interacts with SIRT1 and that treatment with resveratrol significantly enhances this interaction (20).…”

Section: Discussioncontrasting

confidence: 96%

Transgene silencing of the Hutchinson-Gilford progeria syndrome mutation results in a reversible bone phenotype, whereas resveratrol treatment does not show overall beneficial effects

Strandgren¹,

Nasser²,

McKenna³

et al. 2015

The FASEB Journal

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Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder that is most commonly caused by a de novo point mutation in exon 11 of the LMNA gene, c.1824C>T, which results in an increased production of a truncated form of lamin A known as progerin. In this study, we used a mouse model to study the possibility of recovering from HGPS bone disease upon silencing of the HGPS mutation, and the potential benefits from treatment with resveratrol. We show that complete silencing of the transgenic expression of progerin normalized bone morphology and mineralization already after 7 weeks. The improvements included lower frequencies of rib fractures and callus formation, an increased number of osteocytes in remodeled bone, and normalized dentinogenesis. The beneficial effects from resveratrol treatment were less significant and to a large extent similar to mice treated with sucrose alone. However, the reversal of the dental phenotype of overgrown and laterally displaced lower incisors in HGPS mice could be attributed to resveratrol. Our results indicate that the HGPS bone defects were reversible upon suppressed transgenic expression and suggest that treatments targeting aberrant progerin splicing give hope to patients who are affected by HGPS.

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Section: Discussioncontrasting

confidence: 96%

Transgene silencing of the Hutchinson-Gilford progeria syndrome mutation results in a reversible bone phenotype, whereas resveratrol treatment does not show overall beneficial effects

Strandgren¹,

Nasser²,

McKenna³

et al. 2015

The FASEB Journal

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show abstract

“…As we observed dispersion of the nuclear foci formed by the (CUG) n-expanded RNA aggregation after AICAR treatment, the effect of AMPK activation on splicing may be mediated by its interaction with other RNA-binding proteins, such as hnRNP H, which were implicated in foci stability in DM1 (50,51). Hence, one may argue that AMPK deregulation likely contributes to pathogenesis in DM1 muscle by perturbing RNA-binding proteins and thereby accentuating foci stability and mis-splicing events (52)(53)(54). Notably, we cannot rule out that amelioration of muscle relaxation also relies on splicing-independent mechanisms.…”

Section: Discussionmentioning

confidence: 78%

Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I

Brockhoff¹,

Rion²,

Chojnowska³

et al. 2017

Journal of Clinical Investigation

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“…It participates in both constitutive and alternative splicing, RNA metabolism, RNA transport and translation (57). The action of SRSF1 is essential for the regulation of angiogenesis and vascular senescence as it is involved in the generation of several vascular endothelial growth factor (VEGF) isoforms (58) and tissue factor or endoglin (59). It has been also described that SRSF1 overexpression activates the mTOR1 signaling pathway, which plays a significant role in cellular growth and protein translation (59).…”

Section: Discussionmentioning

confidence: 99%

“…The action of SRSF1 is essential for the regulation of angiogenesis and vascular senescence as it is involved in the generation of several vascular endothelial growth factor (VEGF) isoforms (58) and tissue factor or endoglin (59). It has been also described that SRSF1 overexpression activates the mTOR1 signaling pathway, which plays a significant role in cellular growth and protein translation (59). Thus, our results, showing an enhanced expression of SRSF1 in the neurons of the IC region, might reflect the implication of SRSF1 in processes involved in tissue repair after ischemia.…”

Section: Discussionmentioning

confidence: 99%

Single Cell Immuno-Laser Microdissection Coupled to Label-Free Proteomics to Reveal the Proteotypes of Human Brain Cells After Ischemia

García‐Berrocoso

Llombart

Colàs-Campàs

et al. 2018

Molecular & Cellular Proteomics

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Cerebral ischemia entails rapid tissue damage in the affected brain area causing devastating neurological dysfunction. How each component of the neurovascular unit contributes or responds to the ischemic insult in the context of the human brain has not been solved yet. Thus, the analysis of the proteome is a straightforward approach to unraveling these cell proteotypes. In this study, post-mortem brain slices from ischemic stroke patients were obtained corresponding to infarcted (IC) and contralateral (CL) areas. By means of laser microdissection, neurons and blood brain barrier structures (BBB) were isolated and analyzed using label-free quantification. MS data are available via ProteomeXchange with identifier PXD003519. Ninety proteins were identified only in neurons, 260 proteins only in the BBB and 261 proteins in both cell types. Bioinformatics analyses revealed that repair processes, mainly related to synaptic plasticity, are outlined in microdissected neurons, with nonexclusive important functions found in the BBB. A total of 30 proteins showing < 0.05 and fold-change> 2 between IC and CL areas were considered meaningful in this study: 13 in neurons, 14 in the BBB and 3 in both cell types. Twelve of these proteins were selected as candidates and analyzed by immunohistofluorescence in independent brains. The MS findings were completely verified for neuronal SAHH2 and SRSF1 whereas the presence in both cell types of GABT and EAA2 was only validated in neurons. In addition, SAHH2 showed its potential as a prognostic biomarker of neurological improvement when analyzed early in the plasma of ischemic stroke patients. Therefore, the quantitative proteomes of neurons and the BBB (or proteotypes) after human brain ischemia presented here contribute to increasing the knowledge regarding the molecular mechanisms of ischemic stroke pathology and highlight new proteins that might represent putative biomarkers of brain ischemia or therapeutic targets.

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Alteration of splice site selection in the LMNA gene and inhibition of progerin production via AMPK activation

Cited by 12 publications

References 132 publications

Transgene silencing of the Hutchinson-Gilford progeria syndrome mutation results in a reversible bone phenotype, whereas resveratrol treatment does not show overall beneficial effects

Transgene silencing of the Hutchinson-Gilford progeria syndrome mutation results in a reversible bone phenotype, whereas resveratrol treatment does not show overall beneficial effects

Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I

Single Cell Immuno-Laser Microdissection Coupled to Label-Free Proteomics to Reveal the Proteotypes of Human Brain Cells After Ischemia

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