Chronic lithium administration in a mouse model for Krabbe disease

Area of Science:

• Neuroscience
• Lysosomal Storage Disorders
• Pharmacology

Background:

• Krabbe disease (KD), or globoid cell leukodystrophy, is a fatal autosomal recessive lysosomal storage disorder due to galactocerebrosidase (GALC) deficiency.
• Current KD treatments are supportive, lacking a cure, highlighting the need for effective therapeutic strategies.
• Previous in-vitro studies indicated that autophagy inducers, lithium and rapamycin, could ameliorate KD hallmarks.

Purpose of the Study:

• To evaluate the in-vivo efficacy of lithium carbonate in the spontaneous mouse model for Krabbe disease, the Twitcher (TWI) mouse.
• To assess lithium's impact on motor performance, GALC activity, psychosine accumulation, and astrogliosis in TWI mice.
• To investigate lithium's effects on autophagy and β-catenin signaling pathways in the TWI mouse model.

Main Methods:

• Lithium carbonate was administered orally to TWI mice from postnatal day 20.
• Longitudinal monitoring of motor function using grip strength, hanging wire, and rotarod tests.
• Biochemical analyses included GALC activity, psychosine levels, astrogliosis markers, and expression of autophagy and β-catenin pathway markers.

Main Results:

• Lithium treatment did not produce a significant rescue of the TWI phenotype.
• A slight, transient improvement in muscle strength was observed in lithium-treated TWI mice.
• Lithium failed to stimulate autophagy in the TWI mouse central nervous system but suggested restoration of β-catenin activation in the sciatic nerve.

Conclusions:

• Lithium carbonate, administered via drinking water, shows limited therapeutic benefit for Krabbe disease in the TWI mouse model.
• The findings suggest that lithium's mechanism of action in this context may not involve significant autophagy induction in the CNS.
• Further research is warranted to explore lithium's potential and optimize its administration for KD treatment.