Inhibition of the de-myelinating properties of Aicardi-Goutières Syndrome lymphocytes by cathepsin D silencing

A. Pulliero, B. Marengo, M. Longobardi, E. Fazzi, S. Orcesi, I. Olivieri, C. Cereda, C. Domenicotti, U. Balottin, A. Izzotti

Research output: Contribution to journalArticlepeer-review


Molecular mechanisms relating interferon-alpha (IFN-alpha) to brain damage have recently been identified in a microarray analysis of cerebrospinal fluid lymphocytes from patients with Aicardi-Goutières Syndrome (AGS). These findings demonstrate that the inhibition of angiogenesis and the activation of neurotoxic lymphocytes are the major pathogenic mechanisms involved in the brain damage consequent to elevated interferon-alpha levels. Our previous study demonstrated that cathepsin D, a lysosomal aspartyl endopeptidase, is the primary mediator of the neurotoxicity exerted by AGS lymphocytes. Cathepsin D is a potent pro-apoptotic, neurotoxic, and demyelinating protease if it is not properly inhibited by the activities of leukocystatins. In central nervous system white matter, demyelination results from cathepsin over-expression when not balanced by the expression of its inhibitors. In the present study, we used RNA interference to inhibit cathepsin D expression in AGS lymphocytes with the aim of decreasing the neurotoxicity of these cells. Peripheral blood lymphocytes collected from an AGS patient were immortalized and co-cultured with astrocytes in the presence of interferon alpha with or without cathepsin D RNA interference probes. Cathepsin D expression was measured by qPCR, and neurotoxicity was evaluated by microscopy. RNA interference inhibited cathepsin D over-production by 2.6-fold (P

Original languageEnglish
Pages (from-to)957-962
Number of pages6
JournalBiochemical and Biophysical Research Communications
Issue number3
Publication statusPublished - Jan 18 2013


  • Aicardi-Goutières Syndrome
  • Cathepsin D
  • De-myelination
  • Interferon-alpha
  • Lymphocytes
  • RNA interference

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology


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