Nuclear damages and oxidative stress: New Perspectives for laminopathies

G. Lattanzi, S. Marmiroli, A. Facchini, N. M. Maraldi

Research output: Contribution to journalArticle

Abstract

Mutations in genes encoding nuclear envelope proteins, particularly LMNA encoding the A-type lamins, cause a broad range of diverse diseases, referred to as laminopathies. The astonishing variety of diseased phenotypes suggests that different mechanisms could be involved in the pathogenesis of laminopathies. In this review we will focus mainly on two of these pathogenic mechanisms: the nuclear damages affecting the chromatin organization, and the oxidative stress causing un-repairable DNA damages. Alteration in the nuclear profile and in chromatin organization, which are particularly impressive in systemic laminopathies whose cells undergo premature senescence, are mainly due to accumulation of unprocessed prelamin A. The toxic effect of these molecular species, which interfere with chromatin-associated proteins, transcription factors, and signaling pathways, could be reduced by drugs which reduce their farnesylation and/or stability. In particular, inhibitors of farnesyl transferase (FTIs), have been proved to be active in rescuing the altered cellular phenotype, and statins, also in association with other drugs, have been included into pilot clinical trials. The identification of a mechanism that accounts for accumulation of unrepairable DNA damage due to reactive oxygen species (ROS) generation in laminopathic cells, similar to that found in other muscular dystrophies (MDs) caused by altered expression of extracellular matrix (ECM) components, suggests that anti-oxidant therapeutic strategies might prove beneficial to laminopathic patients.

Original languageEnglish
JournalEuropean journal of histochemistry : EJH
Volume56
Issue number4
DOIs
Publication statusPublished - 2012

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Keywords

  • Chromatin
  • Dna damage
  • Laminopathies
  • Muscular dystrophies
  • Nuclear envelope
  • Oxidative stress
  • Progeria

ASJC Scopus subject areas

  • Cell Biology
  • Histology
  • Biophysics

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