MOLECULAR MECHANISMS UNDELYING REST DYSREGULATION IN THE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE) (Englisch)

2019
  • Hochschulschrift  /  Elektronische Ressource

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The development and maturation of the nervous system imply a precise temporal and spatial modulation of gene expression, coordinated by transcriptional enhancers and repressors. In this context, the key role of repressor element 1-silencing transcription factor (REST) is largely known. REST regulates neurogenesis and neuronal identity through cell-specific gene repression, allowing expression of its targets in mature neurons. During neuronal development REST levels are reduced and REST is quiescent in mature neurons, which are able to modulate its expression in response to pathological stimuli. Such dysregulation has been implicated in several neurodegenerative disorders, including Alzheimer’s and Huntington’s diseases, tumors of the central nervous system (CNS) and epilepsy. Our pilot study had indicated that REST is significantly over-expressed in murine chronic experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS), at acute early phase. MS is a CNS autoimmune-mediated disease characterized by chronic inflammation and demyelination in the white and grey matter leading to an impairment of synaptic transmission and network connectivity, with both neuronal and axonal loss. Chronic inflammatory processes that continuously disturb neuro-axonal homeostasis drive neurodegeneration, so the clinical outcome is likely to depend on the balance between inflammation and the remaining capacity for neuronal self-protection and repair. Hence, therapeutic approaches halting neurodegeneration and promoting tissue repair are sorely needed. On this matter, specific targeting of REST-dependent transcription and/or molecular pathways could be an appealing strategy towards therapy in MS. In this project, we have addressed REST expression throughout disease to characterize the role of its unbalance in EAE, assess its potential as biomarker for disease progression, and understand if modulation of REST leads to rescue of EAE phenotype. Starting from these observations, we have first analyzed the expression of REST and its target genes in vivo, during EAE, and in vitro, in the context of neuroinflammation investigating the differential contribution of REST transcripts to REST up-regulation and how this affects its targets. Moreover, in order to study the cellular and molecular pathways involved in the processes of neuroinflammation, we have analyzed REST activity in cell culture, under inflammatory conditions mimicking the EAE microenvironment. Our results support the involvement of REST in the pathological process of EAE, suggesting a possible mechanism of action of REST in the control of its target gene expression in response to neuroinflammation, and demonstrating the involvement of signal pathways regulating REST expression, under these conditions.

  • Titel:
    MOLECULAR MECHANISMS UNDELYING REST DYSREGULATION IN THE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE)
  • Autor / Urheber:
  • Sonstige Beteiligte:
  • Verlag:
    Università degli studi di Genova
  • Erscheinungsjahr:
    2019
  • Medientyp:
    Hochschulschrift
  • Format:
    Elektronische Ressource
  • Sprache:
    Englisch
  • Schlagwörter:
  • Klassifikation:
    DDC:    570
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