Hdac6 deletion delays disease progression in the SOD1G93A mouse model of ALS
Autor: | Ines Taes, Ludo Van Den Bosch, Mieke Timmers, Johan Auwerx, Philip Van Damme, Nicole Hersmus, Wim Robberecht, André Bento-Abreu |
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Rok vydání: | 2013 |
Předmět: |
Male
SOD1 Mice Transgenic Histone Deacetylase 6 SIRT2 Axonal Transport Histone Deacetylases Mice 03 medical and health sciences Sirtuin 2 0302 clinical medicine Tubulin Genetics medicine Animals Axon Amyotrophic lateral sclerosis Molecular Biology Genetics (clinical) 030304 developmental biology 0303 health sciences biology Superoxide Dismutase Amyotrophic Lateral Sclerosis Acetylation General Medicine HDAC6 medicine.disease Molecular biology Axons 3. Good health Cell biology Disease Models Animal medicine.anatomical_structure Disease Progression biology.protein Axoplasmic transport Female Gene Deletion 030217 neurology & neurosurgery |
Zdroj: | Human Molecular Genetics; Vol 22 Human Molecular Genetics |
ISSN: | 1460-2083 0964-6906 |
Popis: | Defects in axonal transport are thought to contribute to the pathogenesis of neurodegenerative disease. Because α-tubulin acetylation facilitates axonal transport, inhibition of the α-tubulin deacetylating enzymes, histone deacetylase 6 (Hdac6) and silent information regulator 2 (Sirt2), is thought to be an interesting therapeutic strategy for these conditions. Amyotrophic lateral sclerosis (ALS) is a one such rapidly progressive and fatal neurodegenerative disorder, in which axonal transport defects have been found in vitro and in vivo. To establish whether the inhibition of Hdac6 or Sirt2 may be of interest for ALS treatment, we investigated whether deleting Hdac6 or Sirt2 from the superoxide dismutase 1, SOD1(G93A) mouse affects the motor neuron degeneration in this ALS model. Deletion of Hdac6 significantly extended the survival of SOD1(G93A) mice without affecting disease onset, and maintained motor axon integrity. This protective effect was associated with increased α-tubulin acetylation. Deletion of Sirt2 failed to affect the disease course, but also did not modify α-tubulin acetylation. These findings show that Hdac6, rather than Sirt2, is a therapeutic target for the treatment of ALS. Moreover, Sirt2 appears not to be a major α-tubulin deacetylase in the nervous system. |
Databáze: | OpenAIRE |
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