Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a very rare fatal disease characterized for accelerated aging. Although the causal agent, a point mutation in LMNA gene, was identified more than a decade ago, the molecular mechanisms underlying HGPS are still not fully understood and, currently, there is no cure for the patients, which die at a mean age of thirteen. With the aim of unraveling non-previously altered molecular pathways in the premature aging process, human cell lines from HGPS patients and from healthy parental controls were studied in parallel using Next-Generation Sequencing (RNAseq) and High-Resolution Quantitative Proteomics (iTRAQ) techniques. After selection of significant proteins and transcripts and crosschecking of the results a small set of protein/transcript pairs were chosen for validation. One of those proteins, ribose-phosphate pyrophosphokinase 1 (PRPS1), is essential for nucleotide synthesis. PRPS1 loss-of-function mutants present lower levels of purine. PRPS1 protein and transcript levels are detected as significantly decreased in HGPS cell lines vs. healthy parental controls. This modulation was orthogonally confirmed by targeted techniques in cell lines and also in an animal model of Progeria, the ZMPSTE24 knock-out mouse. In addition, functional experiments through supplementation with S-adenosyl-methionine (SAMe), a metabolite that is an alternative source of purine, were done. Results indicate that SAMe has a positive effect in the proliferative capacity and reduces senescence-associated Beta-galactosidase staining of the HPGS cell lines. Altogether, our data suggests that nucleotide and, specifically, purine-metabolism, are altered in premature aging, opening a new window for the therapeutic treatment of the disease.
Highlights
Mutations in LMNA gene are the causal agent of subset of genetic diseases affecting mesoderm tissues called laminopathies [1]
Hutchinson Guilford progeria syndrome (HGPS) or progeria is a fatal disease with a very low incidence characterized by a typical clinical picture of elderly pathologies [3]
The mutation causes the occurrence of a cryptic alternative processing site in lamin A, generating a truncated isoform called progerin -PG- or Δ50 lamin A
Summary
Mutations in LMNA gene are the causal agent of subset of genetic diseases affecting mesoderm tissues called laminopathies [1]. This term refers to a highly heterogeneous group of disorders affecting the integrity of the nuclear lamina [2]. The mutation causes the occurrence of a cryptic alternative processing site in lamin A, generating a truncated isoform called progerin -PG- or Δ50 lamin A This aberrant isoform remains farnesylated since the deletion includes the specific recognition sequence for the metalloprotease FACE1 that, in normal conditions removes the farnesylated C-terminal end of the Prelamin A to form the mature lamin A [5]. A mouse model of HGPS, the knock-out deficiency for the metalloproteinase ZMPSTE24, the FACE1 homolog, fails to form mature lamin A, accumulates the permanently farnesylated precursor and recapitulates most of the symptoms of the disease [8]
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