Hutchinson-Gilford Progeria Syndrome: Challenges at Bench and Bedside

Kreienkamp, Ray; Gonzalo, Susana

doi:10.1007/978-981-13-3681-2_15

Cited by 16 publications

(22 citation statements)

References 98 publications

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“…[254][255][256] A phase I/II trial of everolimus in combination with lonafarnib in patients with HGPS and other progeroid laminopathies was started in 2015; the first results are still outstanding and expected for 2020. 66 Sulforaphane, an antioxidant derived from cruciferous vegetables, also stimulated progerin clearance by autophagy in HGPS fibroblasts. 257 Combined treatment of lonafarnib and sulforaphane showed cytotoxic effects in HGPS fibroblasts, whereas intermittent and separate application of the two components in repeated cycles enhanced progerin clearance, normalized nuclear shape and reduced DNA damage in HGPS fibroblasts.…”

Section: Short Syndrome (Mim #269880)mentioning

confidence: 99%

“…259,260 Apart from FTIs and autophagy-activating agents a number of other therapeutic strategies focusing on other potential molecular mechanisms have been investigated in vitro for their potential use in HGPS. 66,253 The ROS scavenger N-acetyl cysteine reduced the level of unrepaired ROS-induced DNA damage and enhanced cell growth. 261 Treatment with methylene blue rescued mitochondrial defects and improved nuclear abnormalities.…”

Section: Short Syndrome (Mim #269880)mentioning

confidence: 99%

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Premature aging disorders: A clinical and genetic compendium

2020

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Progeroid disorders make up a heterogeneous group of very rare hereditary diseases characterized by clinical signs that often mimic physiological aging in a premature manner. Apart from Hutchinson-Gilford progeria syndrome, one of the bestinvestigated progeroid disorders, a wide spectrum of other premature aging phenotypes exist, which differ significantly in their clinical presentation and molecular pathogenesis. Next-generation sequencing (NGS)-based approaches have made it feasible to determine the molecular diagnosis in the early stages of a disease. Nevertheless, a broad clinical knowledge on these disorders and their associated symptoms is still fundamental for a comprehensive patient management and for the interpretation of variants of unknown significance from NGS data sets. This review provides a detailed overview on characteristic clinical features and underlying molecular genetics of well-known as well as only recently identified premature aging disorders and also highlights novel findings towards future therapeutic options. K E Y W O R D S characteristic clinical features, hereditary, premature aging, progeroid disorders 1 | INTRODUCTION Aging is a general biological phenomenon that affects all human beings and results in a functional decline of physiological systems accompanied by an increased risk for chronic ailments with advancing chronological age. 1,2 At the molecular level, aging is for example associated with genomic instability, loss of heterochromatin, and the accumulation of macromolecular damage leading to reduced (stem) cell function and tissue regeneration. 3 Progeroid disorders show many clinical features of aging-associated pathologies and signs similar to physiological aging; however, they occur at earlier ages and often progress rapidly. In many aspects progeria therefore represents a timelapse form of aging. Premature aging processes are mostly segmental in that they involve one or more organs, but do not exhibit all aspects associated with physiological aging. Premature aging signs include, among others, alopecia, hair graying, lipodystrophy, osteoporosis, joint contractures, cataract, hearing loss, atherosclerosis, cardiovascular diseases, diabetes mellitus and malignancies at an early age. In addition to these typical aging phenotypes, progeria patients may also present with growth retardation, developmental delay, and intellectual disability. A more modular view of segmental premature aging syndromes hypothesizes that a cluster of symptoms appearing in several disorders might be due to a common underlying cause-for example, alopecia, osteoporosis and nail atrophy have been proposed to be related to telomere shortening. 4 Research into premature aging disorders aims at understanding the pathogenesis and to develop novel treatment strategies, but also intends to unshadow physiological aging processes since premature aging phenotypes mirror many of the clinical aspects of physiological aging. 3 One of the best-known premature aging disorders is the Hutchinson-Gilford progeria syndr...

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Section: Short Syndrome (Mim #269880)mentioning

confidence: 99%

Section: Short Syndrome (Mim #269880)mentioning

confidence: 99%

Premature aging disorders: A clinical and genetic compendium

2020

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“…Given this hypoglycemia and bradykinesia which preceded death, our lab began to embark on a more thorough metabolic characterization of these mice [80,81]. Interestingly, Lmna G609G/G609G mice have energy alterations well before their ultimate decline.…”

Section: Metabolic Approaches In Progeriamentioning

confidence: 99%

Metabolic Dysfunction in Hutchinson–Gilford Progeria Syndrome

Kreienkamp

Gonzalo

2020

Cells

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Hutchinson–Gilford Progeria Syndrome (HGPS) is a segmental premature aging disease causing patient death by early teenage years from cardiovascular dysfunction. Although HGPS does not totally recapitulate normal aging, it does harbor many similarities to the normal aging process, with patients also developing cardiovascular disease, alopecia, bone and joint abnormalities, and adipose changes. It is unsurprising, then, that as physicians and scientists have searched for treatments for HGPS, they have targeted many pathways known to be involved in normal aging, including inflammation, DNA damage, epigenetic changes, and stem cell exhaustion. Although less studied at a mechanistic level, severe metabolic problems are observed in HGPS patients. Interestingly, new research in animal models of HGPS has demonstrated impressive lifespan improvements secondary to metabolic interventions. As such, further understanding metabolism, its contribution to HGPS, and its therapeutic potential has far-reaching ramifications for this disease still lacking a robust treatment strategy.

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“…Importantly, this study demonstrates a robust effect of calcitriol, hormonal active form of vitamin D, repressing the cGAS/STING/IFN response. Although our previous studies showed this effect in HGPS fibroblasts cultured in the presence of calcitriol for a long period of time (≈90 days) when compared to normal fibroblasts, [2,4,6] now we are able to monitor the activation/repression of these pathways over time. In fact, we find that pre-treatment of cells with calcitriol prevents RAD51 loss, replication stress, and activation of cGAS/STING/IFN pathway upon progerin expression.…”

Section: Discussionmentioning

confidence: 84%

“…To date, more than 450 mutations in the LMNA gene have been associated with degenerative disorders, broadly termed laminopathies, which include muscular dystrophies, neuropathies, lipodystrophies, and progeroid or premature aging diseases such as Hutchinson Gilford progeria syndrome (HGPS). [1,2] In addition, changes in the expression of lamins, especially downregulation, have been associated with poor prognosis in many cancers. [3] These data and the role of lamins in the maintenance of genome stability and function provide evidence for lamins functioning as "genome caretakers."…”

Section: Introductionmentioning

confidence: 99%

Calcitriol Prevents RAD51 Loss and cGAS‐STING‐IFN Response Triggered by Progerin

et al. 2019

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Hutchinson Gilford progeria syndrome (HGPS) is a devastating accelerated aging disease caused by LMNA gene mutation. The truncated lamin A protein produced “progerin” has a dominant toxic effect in cells, causing disruption of nuclear architecture and chromatin structure, genomic instability, gene expression changes, oxidative stress, and premature senescence. It was previously shown that progerin‐induced genomic instability involves replication stress (RS), characterized by replication fork stalling and nuclease‐mediated degradation of stalled forks. RS is accompanied by activation of cGAS/STING cytosolic DNA sensing pathway and STAT1‐regulated interferon (IFN)‐like response. It is also found that calcitriol, the active hormonal form of vitamin D, rescues RS and represses the cGAS/STING/IFN cascade. Here, the mechanisms underlying RS in progerin‐expressing cells and the rescue by calcitriol are explored. It is found that progerin elicits a marked downregulation of RAD51, concomitant with increased levels of phosphorylated‐RPA, a marker of RS. Interestingly, calcitriol prevents RS and activation of the cGAS/STING/IFN response in part through maintenance of RAD51 levels in progerin‐expressing cells. Thus, loss of RAD51 is one of the consequences of progerin expression that can contribute to RS and activation of the IFN response. Stabilization of RAD51 helps explain the beneficial effects of calcitriol in these processes.

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Hutchinson-Gilford Progeria Syndrome: Challenges at Bench and Bedside

Cited by 16 publications

References 98 publications

Premature aging disorders: A clinical and genetic compendium

Premature aging disorders: A clinical and genetic compendium

Metabolic Dysfunction in Hutchinson–Gilford Progeria Syndrome

Calcitriol Prevents RAD51 Loss and cGAS‐STING‐IFN Response Triggered by Progerin

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