Presence and distribution of progerin in HGPS cells is ameliorated by drugs that impact on the mevalonate and mTOR pathways

Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is a rare, premature ageing syndrome in children. HGPS is normally caused by a mutation in the LMNA gene, encoding nuclear lamin A. The classical mutation in HGPS leads to the production of a toxic truncated version of lamin A, progerin, which retains a farnesyl group. Farnesyltransferase inhibitors (FTI), pravastatin and zoledronic acid have been used in clinical trials to target the mevalonate pathway in HGPS patients to inhibit farnesylation of progerin, in order to reduce its toxicity. Some other compounds that have been suggested as treatments include rapamycin, IGF1 and N -acetyl cysteine (NAC). We have analysed the distribution of prelamin A, lamin A, lamin A/C, progerin, lamin B1 and B2 in nuclei of HGPS cells before and after treatments with these drugs, an FTI and a geranylgeranyltransferase inhibitor (GGTI) and FTI with pravastatin and zoledronic acid in combination. Confirming other studies prelamin A, lamin A, progerin and lamin B2 staining was different between control and HGPS fibroblasts. The drugs that reduced progerin staining were FTI, pravastatin, zoledronic acid and rapamycin. However, drugs affecting the mevalonate pathway increased prelamin A, with only FTI reducing internal prelamin A foci. The distribution of lamin A in HGPS cells was improved with treatments of FTI, pravastatin and FTI + GGTI. All treatments reduced the number of cells displaying internal speckles of lamin A/C and lamin B2. Drugs targeting the mevalonate pathway worked best for progerin reduction, with zoledronic acid removing internal progerin speckles. Rapamycin and NAC, which impact on the MTOR pathway, both reduced both pools of progerin without increasing prelamin A in HGPS cell nuclei. Electronic supplementary material The online version of this article (10.1007/s10522-019-09807-4) contains supplementary material, which is available to authorized users.

Molecular and Mechanobiological Pathways Related to the Physiopathology of FPLD2

“…Importantly, treatment with rapamycin, which is a specific mTOR-inhibitor, contributed to an improvement of LMNA –/– mice phenotypes and an elevation of survival, showing that mTOR activation might mediate phenotypes involved in laminopathy diseases. This hypothesis was supported by multiple studies showing that rapamycin or analogue treatments improved the phenotypes of cell and mouse models of LMNA mutation-associated laminopathies [ 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ].…”

Cell immortalization facilitates prelamin A clearance by increasing both cell proliferation and autophagic flux

“…Classical mutations in HGPS lead to the accumulation of a toxic form of lamin A, called progerin, which is a farnesylated form of the protein. Then, the use of different farnesyltransferase inhibitors (FTIs) can reduce its toxicity [ 19 ]. There are multiple lines of research for treating people suffering this disease and very recently it has been approved by US food and drug administration (FDA) to administer in patients from one year of age and above with lonafarnib, which is a FTI [ 20 ].…”

Genome Tectonics: Linking Dynamic Genome Organization with Cellular Nutrients

“…Caused by a single point mutation that results in an aberrant A type lamin protein, called progerin, disrupting the lamina structure concomitantly with the loss of heterochromatin and dysregulation of gene expression patterns genome wide. In addition, HGPS cells not only exhibit LADs disruption [73] but also have entire chromosomes mislocalized within the nuclear volume [74, 75]. The severe phenotypes observed in HGPS cells are an extreme but significant example of the impact of proper organization of the genome on gene regulation and the overall impact this can have on cellular and organismal health.…”

“…The severe phenotypes observed in HGPS cells are an extreme but significant example of the impact of proper organization of the genome on gene regulation and the overall impact this can have on cellular and organismal health. Disruption of cellular nutrient sensing with rapamycin causes progerin degradation leading to increased cellular lifespan and the reversal of several cellular phenotypes of premature cellular aging [75, 76]. Intriguingly, this links nutrient sensing and availability with gene expression and organization, implicating the potential application of dietary strategies and nutrient sensing pathways as targets for both premature aging diseases as well as to combat normal aging processes.…”