Neural Stem Cell Compartments in a Mouse Model of Globoid Cell Leukodystrophy: Implication for Therapeutic Strategies

Globoid cell leukodystrophy (GLD) is a rare genetic lysosomal disorder due to deficiency in the B-galactocerebrosidase (GALC) enzyme. GLD affects mainly children; the prognosis is severe, leading to death few years after the diagnosis. Demyelination is believed to occur as a consequence of Psychosine accumulation and neuroinflammation. Clinical observations in GLD babies suggest that GALC deficiency might affect myelination before overt storage and inflammation, but this issue has been poorly addressed in pre-clinical studies. Similarly, little is known regarding the effect of GALC deficiency on neural stem cell (NSC) in the neurogenic niches during CNS development. The goal of this study was to extensively characterize the role of GALC in regulating the function of NSC niches during the disease progression in Twitcher (Twi) mice, a relevant GLD model. By morphological and functional analysis we showed altered cellular organization and loss of proliferating neuroblasts in the subventricular zone (SVZ) niche of Twi mice as a function of disease progression. These data were confirmed by in vitro experiments showing decreased numbers of primary neurospheres generated from Twi NSC/progenitors. Both defects were rescued to normal levels in symptomatic Twi mice chronically treated with anti-inflammatory drugs. These results, as well as the up-regulation of several inflammatory molecules observed in Twi brains starting from the early symptomatic stage, suggested a major contribution by neuroinflammation at the late stages of the disease. However, these data did not rule out a direct contribution of GALC deficiency nor do they exclude a role of GALC in maintaining a functional niche during CNS development. Indeed, our results indicate decreased proliferation and maturation of NSC/progenitors derived from asymptomatic Twi mice, suggesting that GALC deficiency might lead to neurogenic impairment independently from CNS inflammation. These results improve our understanding of the pathogenic mechanisms of GLD with important implications for therapy