Increased SOD1 association with chromatin, DNA damage, p53 activation, and apoptosis in a cellular model of SOD1-linked ALS

Livea F. Barbosa, Fernanda M. Cerqueira, Antero F A Macedo, Camila C M Garcia, José Pedro F Angeli, Robert I. Schumacher, Mari Cleide Sogayar, Ohara Augusto, Maria Teresa Carrí, Paolo Di Mascio, Marisa H G Medeiros

Research output: Contribution to journalArticle

Abstract

Mutations in the gene encoding cytosolic Cu,Zn-superoxide dismutase (SOD1) have been linked to familial amyotrophic lateral sclerosis (FALS). However the molecular mechanisms of motor neuron death are multi-factorial and remain unclear. Here we examined DNA damage, p53 activity and apoptosis in SH-SY5Y human neuroblastoma cells transfected to achieve low-level expression of either wild-type or mutant Gly93→Ala (G93A) SOD1, typical of FALS. DNA damage was investigated by evaluating the levels of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) and DNA strand breaks. Significantly higher levels of DNA damage, increased p53 activity, and a greater percentage of apoptotic cells were observed in SH-SY5Y cells transfected with G93A SOD1 when compared to cells overexpressing wild-type SOD1 and untransfected cells. Western blot, FACS, and confocal microscopy analysis demonstrated that G93A SOD1 is present in the nucleus in association with DNA. Nuclear G93A SOD1 has identical superoxide dismutase activity but displays increased peroxidase activity when compared to wild-type SOD1. These results indicate that the G93A mutant SOD1 association with DNA might induce DNA damage and trigger the apoptotic response by activating p53. This toxic activity of mutant SOD1 in the nucleus may play an important role in the complex mechanisms associated with motor neuron death observed in ALS pathogenesis.

Original languageEnglish
Pages (from-to)462-471
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1802
Issue number5
DOIs
Publication statusPublished - May 2010

Keywords

  • ALS
  • DNA damage
  • Nucleus
  • P53
  • SOD1

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine

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  • Cite this

    Barbosa, L. F., Cerqueira, F. M., Macedo, A. F. A., Garcia, C. C. M., Angeli, J. P. F., Schumacher, R. I., Sogayar, M. C., Augusto, O., Carrí, M. T., Di Mascio, P., & Medeiros, M. H. G. (2010). Increased SOD1 association with chromatin, DNA damage, p53 activation, and apoptosis in a cellular model of SOD1-linked ALS. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1802(5), 462-471. https://doi.org/10.1016/j.bbadis.2010.01.011