title: The galactocerebrosidase enzyme contributes to maintain a functional neurogenic niche during early post-natal CNS development.
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.
authors.affiliation: San Raffaele Scientific Institute, Telethon Institute for Gene Therapy, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Santambrogio
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ricca
authors.forename: Claudio
authors.initials: C
authors.lastname: Maderna
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ieraci
authors.forename: Massimo
authors.initials: M
authors.lastname: Aureli
authors.forename: Sandro
authors.initials: S
authors.lastname: Sonnino
authors.forename: Willem
authors.initials: W
authors.lastname: Kulik
authors.forename: Patrizia
authors.initials: P
authors.lastname: Aimar
authors.forename: Luca
authors.initials: L
authors.lastname: Bonfanti
authors.forename: Sabata
authors.initials: S
authors.lastname: Martino
authors.forename: Angela
authors.initials: A
authors.lastname: Gritti
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D017690:Cell Transplantation; D002490:Central Nervous System / Q000201:enzymology / Q000254:growth & development; D002648:Child; D004195:Disease Models, Animal; D005698:Galactosylceramidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D007965:Leukodystrophy, Globoid Cell / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000201:enzymology / Q000378:metabolism
chemical_list: D005698:Galactosylceramidase