Status of treatment strategies for Hutchinson–Gilford progeria syndrome with a focus on prelamin: A posttranslational modification

Chen, Xue; Yao, Haidong; Andrés, Vicente; Bergö, Martin O.; Kashif, Muhammad

doi:10.1111/bcpt.13770

Cited by 6 publications

(5 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Some compounds that inhibit p38/MAPK have been suggested to aid in the treatment of WS, however the potential therapeutic effects of inhibiting other senescence pathways have not yet been investigated for WS [35][36][37]. Only lonafarnib, a farnesyltransferase inhibitor, is approved for HGPS, but several senotherapeutic compounds like rapamycin have been identified as having potential in in vitro research [38][39][40][41][42]. The action of the farnesyltransferase is able to improve the persistent farnesylation of the aberrant Lamin A protein caused by HGPS [38].…”

Section: Introductionmentioning

confidence: 99%

Senescence, regulators of alternative splicing and effects of trametinib treatment in progeroid syndromes

Bramwell,

Harries

2023

GeroScience

View full text Add to dashboard Cite

Progeroid syndromes such as Hutchinson Gilford Progeroid syndrome (HGPS), Werner syndrome (WS) and Cockayne syndrome (CS), result in severely reduced lifespans and premature ageing. Normal senescent cells show splicing factor dysregulation, which has not yet been investigated in syndromic senescent cells. We sought to investigate the senescence characteristics and splicing factor expression profiles of progeroid dermal fibroblasts. Natural cellular senescence can be reversed by application of the senomorphic drug, trametinib, so we also investigated its ability to reverse senescence characteristics in syndromic cells. We found that progeroid cultures had a higher senescence burden, but did not always have differences in levels of proliferation, DNA damage repair and apoptosis. Splicing factor gene expression appeared dysregulated across the three syndromes. 10 µM trametinib reduced senescent cell load and affected other aspects of the senescence phenotype (including splicing factor expression) in HGPS and Cockayne syndromes. Werner syndrome cells did not demonstrate changes in in senescence following treatment. Splicing factor dysregulation in progeroid cells provides further evidence to support this mechanism as a hallmark of cellular ageing and highlights the use of progeroid syndrome cells in the research of ageing and age-related disease. This study suggests that senomorphic drugs such as trametinib could be a useful adjunct to therapy for progeroid diseases.

show abstract

Section: Introductionmentioning

confidence: 99%

Senescence, regulators of alternative splicing and effects of trametinib treatment in progeroid syndromes

Bramwell,

Harries

2023

GeroScience

View full text Add to dashboard Cite

show abstract

“…suffering from this disease. Lonafarnib was subsequently approved for treatment of patients with HGPS (17). Thus, FTI also have clinical relevance in other medical contexts than originally anticipated (5).…”

Section: Discussionmentioning

confidence: 99%

“…However, additional targets of Farnesyltransferase have been identified recently indicating that FTI may modulate additional relevant pathways apart from Ras ( 5 , 6 ). Indeed, it was discovered that the disease-causing protein progerin in Hutchinson-Gilford progeria syndrome (HGPS) harbors a target site for farnesylation ( 17 ). Farnesylation of progerin causes accumulation of this aberrant protein.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Farnesyltransferase-inhibitors exert in vitro immunosuppressive capacity by inhibiting human B-cells

Xu,

Dolff,

Mülling

et al. 2023

Front. Transplant.

View full text Add to dashboard Cite

ObjectivesFarnesyltransferase inhibitors (FTI), which inhibit the prenylation of Ras GTPases, were developed as anti-cancer drugs. As additional target proteins for prenylation were identified in the past, it is likely that FTI have potential value for therapeutic purposes beyond cancer. The effect of FTI on B-cells remains unclear. To address this issue, we investigated the effects of in vitro FTI treatment on effector and regulatory B-cells in healthy controls and renal transplant patients.MethodsFor this purpose, B-cells were isolated from the peripheral blood of healthy controls and renal transplant patients. Purified B-cells were stimulated via Toll-like-receptor 9 (TLR-9) in the presence or absence of FTI. Regulatory functions, such as IL-10 and Granzyme B (GrB) secretion, were assessed by flow cytometry. In addition, effector B-cell functions, such as plasma cell formation and IgG secretion, were studied.ResultsThe two FTI Lonafarnib and tipifarnib both suppressed TLR-9-induced B-cell proliferation. Maturation of IL-10 producing B-cells was suppressed by FTI at high concentrations as well as induction of GrB-secreting B-cells. Plasma blast formation and IgG secretion were potently suppressed by FTI. Moreover, purified B-cells from immunosuppressed renal transplant patients were also susceptible to FTI-induced suppression of effector functions, evidenced by diminished IgG secretion.ConclusionFTI suppress in vitro B-cell proliferation and plasma cell formation while partially preserving IL-10 as well as GrB production of B-cells. Thus, FTI may have immunosuppressive capacity encouraging further studies to investigate the potential immunomodulatory value of this agent.

show abstract

“…However, prelamin A levels are transiently increased upon oxidative stress ( Liu et al, 2013 ; Cenni et al, 2014 ) and farnesylated prelamin A is elevated during myogenic differentiation and in differentiated muscle cells ( Mattioli et al, 2011 ). On the other hand, LMNA gene mutations may affect prelamin A processing leading to toxic accumulation of different lamin A precursors, a condition that causes lipodystrophic and progeroid laminopathies ( Capanni et al, 2005 ; Filesi et al, 2005 ; Cenni et al, 2014 ; Cenni et al, 2020a ; Benedicto et al, 2022 ; Chen et al, 2022 ; Wang et al, 2022 ). Moreover, toxic levels of prelamin A are accumulated in tissues subjected to stress due to pathological conditions as occurs in the cardiovascular system of patients affected by chronic kidney disease ( Ragnauth et al, 2010 ; Liu et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

The role of prelamin A post-translational maturation in stress response and 53BP1 recruitment

Capanni

Schena²,

Giampietro³

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Lamin A is a main constituent of the nuclear lamina and contributes to nuclear shaping, mechano-signaling transduction and gene regulation, thus affecting major cellular processes such as cell cycle progression and entry into senescence, cellular differentiation and stress response. The role of lamin A in stress response is particularly intriguing, yet not fully elucidated, and involves prelamin A post-translational processing. Here, we propose prelamin A as the tool that allows lamin A plasticity during oxidative stress response and permits timely 53BP1 recruitment to DNA damage foci. We show that while PCNA ubiquitination, p21 decrease and H2AX phosphorylation occur soon after stress induction in the absence of prelamin A, accumulation of non-farnesylated prelamin A follows and triggers recruitment of 53BP1 to lamin A/C complexes. Then, the following prelamin A processing steps causing transient accumulation of farnesylated prelamin A and maturation to lamin A reduce lamin A affinity for 53BP1 and favor its release and localization to DNA damage sites. Consistent with these observations, accumulation of prelamin A forms in cells under basal conditions impairs histone H2AX phosphorylation, PCNA ubiquitination and p21 degradation, thus affecting the early stages of stress response. As a whole, our results are consistent with a physiological function of prelamin A modulation during stress response aimed at timely recruitment/release of 53BP1 and other molecules required for DNA damage repair. In this context, it becomes more obvious how farnesylated prelamin A accumulation to toxic levels alters timing of DNA damage signaling and 53BP1 recruitment, thus contributing to cellular senescence and accelerated organismal aging as observed in progeroid laminopathies.

show abstract

Status of treatment strategies for Hutchinson–Gilford progeria syndrome with a focus on prelamin: A posttranslational modification

Cited by 6 publications

References 44 publications

Senescence, regulators of alternative splicing and effects of trametinib treatment in progeroid syndromes

Senescence, regulators of alternative splicing and effects of trametinib treatment in progeroid syndromes

Farnesyltransferase-inhibitors exert in vitro immunosuppressive capacity by inhibiting human B-cells

The role of prelamin A post-translational maturation in stress response and 53BP1 recruitment

Contact Info

Product

Resources

About