Metabolic Dysfunction in Hutchinson–Gilford Progeria Syndrome

Kreienkamp, Ray; Gonzalo, Susana

doi:10.3390/cells9020395

Cited by 31 publications

(27 citation statements)

References 111 publications

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“…None of currently available drugs was able to counteract adipose tissue loss, either in less severe LMNA ‐linked lipodystrophies (Araujo‐Vilar & Santini, 2019) or in HGPS (Gordon et al, 2018). On the other hand, in Lmna G609G / G609G mice subjected to high fat diet, an impressive life span extension was obtained (Kreienkamp et al, 2019; Kreienkamp & Gonzalo, 2020), suggesting a main role of adipose tissue loss in HGPS pathogenesis. Thus, amelioration of white adipose tissue condition by tocilizumab might contribute to the overall improvement of health status here observed in progeroid mice.…”

Section: Discussionmentioning

confidence: 99%

“…Cell intrinsic and cell-independent mechanisms play a synergistic role in HGPS pathogenesis (Bidault et al, 2020;Del Campo et al, 2019;Cenni et al, 2020;Kreienkamp et al, 2016Kreienkamp et al, , 2018Kreienkamp et al, , 2019Kreienkamp & Gonzalo, 2020;Osmanagic-Myers et al, 2019). Thus, an efficient therapeutic strategy needs to counteract both mechanism types.…”

Section: Discussionmentioning

confidence: 99%

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Interleukin‐6 neutralization ameliorates symptoms in prematurely aged mice

et al. 2021

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Hutchinson–Gilford progeria syndrome (HGPS) causes premature aging in children, with adipose tissue, skin and bone deterioration, and cardiovascular impairment. In HGPS cells and mouse models, high levels of interleukin‐6, an inflammatory cytokine linked to aging processes, have been detected. Here, we show that inhibition of interleukin‐6 activity by tocilizumab, a neutralizing antibody raised against interleukin‐6 receptors, counteracts progeroid features in both HGPS fibroblasts and LmnaG609G/G609G progeroid mice. Tocilizumab treatment limits the accumulation of progerin, the toxic protein produced in HGPS cells, rescues nuclear envelope and chromatin abnormalities, and attenuates the hyperactivated DNA damage response. In vivo administration of tocilizumab reduces aortic lesions and adipose tissue dystrophy, delays the onset of lipodystrophy and kyphosis, avoids motor impairment, and preserves a good quality of life in progeroid mice. This work identifies tocilizumab as a valuable tool in HGPS therapy and, speculatively, in the treatment of a variety of aging‐related disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Interleukin‐6 neutralization ameliorates symptoms in prematurely aged mice

et al. 2021

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“…Envelopathies display a large variety of clinical symptoms including metabolic syndrome, muscular dystrophy, lipodystrophy, neuropathy, and progeria (premature aging), among many others. Lipodystrophies result in an array of metabolic complications as insulin resistance, type 2 diabetes, hypertriglyceridemia, and hepatic steatosis [ 59 , 60 , 61 , 62 , 63 ]. Interestingly, patients with metabolic syndrome also exhibit an unusual high prevalence of laminopathies [ 64 ].…”

Section: Nuclear Envelope Diversity and Abnormalitiesmentioning

confidence: 99%

Nuclear Envelope Integrity in Health and Disease: Consequences on Genome Instability and Inflammation

Gauthier

Comaills

2021

IJMS

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The dynamic nature of the nuclear envelope (NE) is often underestimated. The NE protects, regulates, and organizes the eukaryote genome and adapts to epigenetic changes and to its environment. The NE morphology is characterized by a wide range of diversity and abnormality such as invagination and blebbing, and it is a diagnostic factor for pathologies such as cancer. Recently, the micronuclei, a small nucleus that contains a full chromosome or a fragment thereof, has gained much attention. The NE of micronuclei is prone to collapse, leading to DNA release into the cytoplasm with consequences ranging from the activation of the cGAS/STING pathway, an innate immune response, to the creation of chromosomal instability. The discovery of those mechanisms has revolutionized the understanding of some inflammation-related diseases and the origin of complex chromosomal rearrangements, as observed during the initiation of tumorigenesis. Herein, we will highlight the complexity of the NE biology and discuss the clinical symptoms observed in NE-related diseases. The interplay between innate immunity, genomic instability, and nuclear envelope leakage could be a major focus in future years to explain a wide range of diseases and could lead to new classes of therapeutics.

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“…They tend to develop arteriosclerosis in childhood, which greatly increases the risk of ischemic heart disease at a young age. These serious cardiovascular complications can be life-threatening events for affected patients and the cause of early death between 10 and 15 years of age[ 3 ]. Based on previous studies, the prevalence of HGPS is estimated to be approximately 1 in 18 million[ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Long-term survival in a patient with Hutchinson-Gilford progeria syndrome and osteosarcoma: A case report

Hayashi¹,

Yamamoto²,

Takeuchi³

et al. 2021

WJCC

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BACKGROUND Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare disease characterized by the rapid appearance of aging with an onset in childhood. Serious cardiovascular complications can be life-threatening events for affected patients and the cause of early death. Herein we report a HGPS patient with osteosarcoma hat was successfully managed and is alive 13 years after the diagnosis. This is the first report describing the detailed surgical procedure and long-term follow-up of osteosarcoma in a patient with HGPS. CASE SUMMARY The patient was diagnosed with HGPS at 5 years of age with typical features and was referred to our department with a suspected bone tumor of the left proximal tibia at the age of 18. Open biopsy of the tibial bone tumor revealed a conventional fibroblastic osteosarcoma. We have developed and performed a freezing technique using liquid nitrogen for tumor reconstruction. This technique overcame the small size of the tibia for megaprosthesis and avoided amputation and limb salvage was achieved 13 years post-operatively. Although the patient had a number of surgical site complications, such as wound dehiscence, and superficial and deep infections due to vulnerable skin in HGPS, no recurrence or metastases were detected for 13 years, and she walks assisted by crutches. Her general health was good at the latest follow-up at 31 years of age. CONCLUSION A HGPS patient with osteosarcoma was successfully managed and she was alive 13 years after the diagnosis.

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Metabolic Dysfunction in Hutchinson–Gilford Progeria Syndrome

Cited by 31 publications

References 111 publications

Interleukin‐6 neutralization ameliorates symptoms in prematurely aged mice

Interleukin‐6 neutralization ameliorates symptoms in prematurely aged mice

Nuclear Envelope Integrity in Health and Disease: Consequences on Genome Instability and Inflammation

Long-term survival in a patient with Hutchinson-Gilford progeria syndrome and osteosarcoma: A case report

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