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.
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.
|Titolo:||The galactocerebrosidase enzyme contributes to maintain a functional neurogenic niche during early post-natal CNS development|
|Parole Chiave:||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|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
Settore BIO/11 - Biologia Molecolare
Settore BIO/13 - Biologia Applicata
Settore BIO/14 - Farmacologia
|Data di pubblicazione:||2012|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1093/hmg/dds313|
|Appare nelle tipologie:||01 - Articolo su periodico|