HDAC6 inhibition as a mechanism to prevent neurodegeneration in the mSOD1G93A mouse model of ALS

• Published in: Heliyon 2024-07, Vol.10 (14), p.e34587, Article e34587
• Main Authors: Phipps, Andrew J., Dwyer, Samuel, Collins, Jessica M., Kabir, Fariha, Atkinson, Rachel AK, Chowdhury, Md Anisuzzaman, Matthews, Lyzette, Dixit, Deepika, Terry, Rhiannon S., Smith, Jason, Gueven, Nuri, Bennett, William, Cook, Anthony L., King, Anna E., Perry, Sharn
• Format: Article
• Language: English
• Subjects: ACY-738; ALS; Axon degeneration; Neurofilament; Riluzole; SOD1
• ISSN: 2405-8440; 2405-8440
• DOI: 10.1016/j.heliyon.2024.e34587

The loss of upper and lower motor neurons, and their axons is central to the loss of motor function and death in amyotrophic lateral sclerosis (ALS). Due to the diverse range of genetic and environmental factors that contribute to the pathogenesis of ALS, there have been difficulties in developing effective therapies for ALS. One emerging dichotomy is that protection of the neuronal cell soma does not prevent axonal vulnerability and degeneration, suggesting the need for targeted therapeutics to prevent axon degeneration. Post-translational modifications of protein acetylation can alter the function, stability and half-life of individual proteins, and can be enzymatically modified by histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs), which add, or remove acetyl groups, respectively. Maintenance of post-translational microtubule acetylation has been suggested as a mechanism to stabilize axons, prevent axonal loss and neurodegeneration in ALS. This study used an orally dosed potent HDAC6 inhibitor, ACY-738, prevent deacetylation and stabilize microtubules in the mSOD1G93A mouse model of ALS. Co-treatment with riluzole was performed to determine any effects or drug interactions and potentially enhance preclinical research translation. This study shows ACY-738 treatment increased acetylation of microtubules in the spinal cord of mSOD1G93A mice, reduced lower motor neuron degeneration in female mice, ameliorated reduction in peripheral nerve axon puncta size, but did not prevent overt motor function decline. The current study also shows peripheral nerve axon puncta size to be partially restored after treatment with riluzole and highlights the importance of co-treatment to measure the potential effects of therapeutics in ALS. •ACY-738 inhibits HDAC6 and leads to increased microtubule acetylation in spinal cord of mSOD1G93A mice.•ACY-738 treatment reduces lower motor neuron degeneration in the lumbar spinal cord of mSOD1G93A mice.•ACY-738 treatment restores peripheral nerve axon puncta size of mSOD1G93A mice.•ACY-738 treatment does not prevent overt motor function decline mSOD1G93A mice.•Riluzole treatment partially restores peripheral nerve axon puncta size in mSOD1G93A mice.