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

Frontiers in Molecular Neuroscience

Molecular Neuroscience

Olga Golonzhka¹  Matthew Jarpe¹  Marlene M. Morgado²  Sandra O. Braz²  Marta I. Pereira²  Ana C. Monteiro²  Joana Nogueira-Rodrigues²  Monica M. Sousa²  Pedro Brites³ 

[1] Acetylon Pharmaceuticals Inc., Boston, MA, United States;Nerve Regeneration Group, Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal;NeuroLipid Biology Group, Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal;

关键词: axonal transport;    HDAC6;    Krabbe disease;    leukodystrophy;    microtubule stability;    tubulin acetylation;    Twitcher mice;   

DOI  :  10.3389/fnmol.2023.1231659

 received in 2023-05-30, accepted in 2023-07-12,  发布年份 2023

来源: Frontiers

【 摘 要 】

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

【 授权许可】

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Copyright © 2023 Braz, Morgado, Pereira, Monteiro, Golonzhka, Jarpe, Brites, Sousa and Nogueira-Rodrigues.