The galactocerebrosidase enzyme contributes to maintain a functional neurogenic niche during early post-natal CNS development

Sara Santambrogio, Alessandra Ricca, Claudio Maderna, Alessandro Ieraci, Massimo Aureli, Sandro Sonnino, Willem Kulik, Patrizia Aimar, Luca Bonfanti, Sabata Martino, Angela Gritti

Research output: Contribution to journalArticle

Abstract

We report a novel role for the lysosomal galactosylceramidase (GALC), which is defective in globoid cell leukodystrophy (GLD), in maintaining a functional post-natal subventricular zone (SVZ) neurogenic niche. We show that proliferation/self-renewal of neural stem cells (NSCs) and survival of their neuronal and oligodendroglial progeny are impaired in GALC-deficient mice. Using drugs to modulate inflammation and gene transfer to rescue GALC expression and activity, we show that lipid accumulation resulting from GALC deficiency acts as a cell-autonomous pathogenic stimulus in enzyme-deficient NSCs and progeny before upregulation of inflammatory markers, which later sustain a non-cell-autonomous dysfunction. Importantly, we provide evidence that supply of functional GALC provided by neonatal intracerebral transplantation of NSCs ameliorates the functional impairment in endogenous SVZ cells. Insights into the mechanism/s underlying GALC-mediated regulation of early post-natal neurogenic niches improve our understanding of the multi-component pathology of GLD. The occurrence of a restricted period of SVZ neurogenesis in infancy supports the implications of our study for the development of therapeutic strategies to treat this severe pediatric neurodegenerative disorder.

Original languageEnglish
Article numberdds313
Pages (from-to)4732-4750
Number of pages19
JournalHuman Molecular Genetics
Volume21
Issue number21
DOIs
Publication statusPublished - Nov 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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    Santambrogio, S., Ricca, A., Maderna, C., Ieraci, A., Aureli, M., Sonnino, S., Kulik, W., Aimar, P., Bonfanti, L., Martino, S., & Gritti, A. (2012). The galactocerebrosidase enzyme contributes to maintain a functional neurogenic niche during early post-natal CNS development. Human Molecular Genetics, 21(21), 4732-4750. [dds313]. https://doi.org/10.1093/hmg/dds313