Data from: Chronic Rapamycin administration via drinking water mitigates the pathological phenotype in a Krabbe disease mouse model through autophagy activation.

ABSTRACT 
Krabbe disease (KD) is a rare disorder caused by a deficiency of the lysosomal enzyme galactosylceramidase (GALC), resulting in the accumulation of the cytotoxic metabolite psychosine (PSY) in the nervous system. This accumulation triggers demyelination and neurodegeneration. Despite ongoing research, the underlying pathogenic mechanisms remain incompletely understood, and there is currently no cure available.
Previous studies from our lab revealed the presence of autophagy dysfunctions in KD pathogenesis, as evidenced by the presence of p62-tagged protein aggregates in the brains of KD mice and increased p62 levels in the KD sciatic nerve. We also demonstrated that the autophagy inducer Rapamycin (RAPA) can partially restore the wild-type (WT) phenotype in KD primary cells by reducing the number of p62 aggregates.
In this study, we tested RAPA in the Twitcher (TWI) mouse, a spontaneous KD mouse model. We administered the drug ad libitum via drinking water (15 mg/L) starting from post-natal day (PND) 21-23. We longitudinally monitored the motor performance of the mice through grip strength and rotarod tests, along with various biochemical parameters related to KD pathogenesis (i.e. autophagy markers expression, myelination, astrogliosis, and PSY accumulation).
Our findings demonstrate that RAPA significantly enhances motor functions at specific treatment time points and reduces astrogliosis in TWI brain, spinal cord, and sciatic nerves. Using western blot and immunohistochemistry, we observed a decrease in p62 aggregates in TWI nervous tissues, which corroborates our earlier in-vitro results. Furthermore, RAPA treatment partially reduces PSY levels in the spinal cord.
In conclusion, our results support the consideration of RAPA as a supportive therapy for KD. Importantly, as RAPA is already available in pharmaceutical formulations for clinical use, its potential for KD treatment can be promptly evaluated in clinical trials.