The galactocerebrosidase enzyme contributes to maintain a functional neurogenic niche during early post-natal CNS development
Articolo
Data di Pubblicazione:
2012
Citazione:
The galactocerebrosidase enzyme contributes to maintain a functional neurogenic niche during early post-natal CNS development / S. Santambrogio, A. Ricca, C. Maderna, A. Ieraci, M. Aureli, S. Sonnino, W. Kulik, P. Aimar, L. Bonfanti, S. Martino, A. Gritti. - In: HUMAN MOLECULAR GENETICS. - ISSN 0964-6906. - 21:21(2012), pp. dds313.4732-dds313.4750. [10.1093/hmg/dds313]
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
animals; cell proliferation; cell transplantation; child; disease models, animal; gene expression regulation, developmental; gene transfer techniques; genetic therapy; humans; mice; neurons; oligodendroglia; central nervous system; galactosylceramidase; leukodystrophy, globoid cell; neural stem cells; genetics; genetics (clinical); molecular biology
Elenco autori:
S. Santambrogio, A. Ricca, C. Maderna, A. Ieraci, M. Aureli, S. Sonnino, W. Kulik, P. Aimar, L. Bonfanti, S. Martino, A. Gritti
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