Globoid cell Leukodystrophy Disease (GLD) is a neurodegenerative life-threatening disease caused by genetic defects in the lysosomal enzyme galactosylceramidase (GALC). There is no cure for GLD. Treatment options are still very poor. Here, we consider GLD pathogenesis from an entirely new angle, changing the focus from the neurons and oligodendrocytes to the non-parenchymal brain cells. Meninges host neural stem/precursor cells with neuronal differentiation potential and are emerging as injury-induced site in many neurodegenerative diseases. To study the involvement of meninges in GLD pathogenesis and progression, we assessed at pre-onset, onset and late stage of the GLD the activation of meningeal immune cell and neural precursors (NPCs) in Twitcher mice, a mouse model of GLD. We found at pre-onset a GLD-induced activation in meninges consisting of several immune cell types increased, including monocytes and neutrophils. Moreover, GLD-induced increase and modification of the distribution and phenotype of NPCs present in meninges. These data demonstrate, for the first time, that GLD-induced alterations are present in brain meninges before the clinical onset and the neural parenchyma involvement.Furthermore, we performed proof of concept of the efficacy and safety of supra-physiological GALC expression first in murine and then in human neurons derived from somatic adult meningeal NPCs. LV-GALC transduced meningeal NPCs, meningeal derived-neurons, and -brain organoids, which expressed supra-physiological level of GALC showed stem cell and multipotent neural differentiation potential both in mouse and human.