Globoid Cell Leukodystrophy (GLD) is a rare, hereditary disorder (with a frequency of about 1/100000 newborns) triggered by a deficit of the lysosomal enzyme galactosylceramidase (GALC) and characterized by the accumulation of galactosylsphingosine (psychosine, PSY) in the nervous system. PSY is a cytotoxic sphingolipid, which leads to the widespread degeneration of oligodendrocytes and Schwann cells, causing demyelination. Little is known about the molecular mechanisms by which PSY imparts toxicity and there is currently no cure available for GLD. The early-infantile and most widespread form of this lysosomal storage disorder (LSD) is degenerative, rapidly progressive and lethal. Bone marrow transplantation is currently the only clinically applied method to treat GLD, but gene therapy has yielded good results in experimental models. However, the recent literature strongly suggests that GALC-deficiency correction is not sufficient to completely rescue the GLD phenotype. Thus, supportive therapies
specifically addressing secondary targets of the disease might be needed to improve the final therapeutic outcome.

Autophagy, although much studied for many LSDs and neurodegenerative diseases (NDs), has been poorly investigated in GLD. Autophagy dysregulation has been only recently demonstrated, by us and others, in two in vitro GLD cell models.

Here, given our previous results and the wide data form literature showing autophagy activation as a promising therapeutic strategy for NDs and LSDs, we propose the pre-clinical testing of two autophagy activators in the naturally occurring murine model of GLD, the Twitcher mouse (TWI). Specifically, we aim to test in the TWI mouse the effects of Lithium, Rapamycin and of their combination, studying the rescue of a complete set of behavioural and biochemical parameters.

Certainly, this study will be very useful to deeply understand the role of autophagy in the molecular pathogenesis of GLD. Furthermore, in case of positive results, therapy will be readily applicable to humans for clinical testing, thanks to the fact that both tested drugs are already available as pharmaceutical preparations. Therefore, in a forward-looking vision, Lithium and/or Rapamycin could be used in combination with a main GALC-deficiency correcting therapy (as gene therapy and/or enzyme replacement therapy) to help in the achievement of a complete GLD phenotype rescue.

Project financed by ELA up to: 28 000 €