HDAC-6 inhibition ameliorates the early neuropathology in a mouse model of Krabbe disease

• DOI: 10.1101/2023.05.01.538924
• Publication Date: 2023-05-02T05:20:14Z
• Authors: Sandra O. Braz; Marlene M. Morgado; Marta I. Pereira; Ana C. Monteiro; Olga Golonzhka; Matthew Jarpe; Pedro Brites; Monica M. Sousa; Joana Nogueira-Ro...
• Keywords: Neuropathology; Lysosomal storage disease; Krabbe disease; Axoplasmic transport

Abstract In Krabbe disease (KD), mutations in β-galactosylceramidase (GALC), a lysosomal enzyme responsible for the catabolism of galactolipids, lead to accumulation its substrates galactocerebroside and psychosine. This neurologic condition is characterized by severe progressive demyelination together with neuron-autonomous defects degeneration. Twitcher mice mimic infantile form KD, which most common human disease. The CNS PNS present demyelination, axonal loss neuronal including decreased levels acetylated tubulin, microtubule stability impaired transport. Here, we tested whether inhibiting α-tubulin deacetylase HDAC6 specific inhibitor, ACY-738, was able counteract early neuropathology mice. Our data show that delivery ACY-738 corrects low tubulin nervous system. Furthermore, it reverts myelinated axons sciatic nerve optic when administered from birth postnatal day 9, suggesting drug holds neuroprotective properties. extended delayed degeneration ameliorated general presentation effective rescuing neurons, stabilizing dynamics increasing transport mitochondria. Overall, our results support has effect KD should be considered as an add-on therapy combined strategies targeting metabolic correction.