期刊
HUMAN MOLECULAR GENETICS
卷 22, 期 9, 页码 1783-1790出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddt028
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资金
- University of Leuven (KU Leuven) [GOA/11/014]
- Interuniversity Attraction Poles (IUAP) of the Belgian Federal Science Policy Office [P7/16]
- European Community [259867]
- Frick Foundation for ALS Research, ALS Therapy Alliance
- Fund for Scientific Research, Flanders (FWO-F) [G.0440.12N]
- Ecole Polytechnique Federale de Lausanne
- EU Ideas program [ERC-2008-AdG-23118]
- L'Association Francaise contre les Myopathies [14471]
- E von Behring Chair for Neuromuscular and Neurodegenerative Disorders
- Agency for Innovation by Science and Technology in Flanders (IWT)
- Nestle ' Chair in Energy Metabolism
- Velux Stiftung
- and the Swiss National Science Foundation [31003A-124713]
Defects in axonal transport are thought to contribute to the pathogenesis of neurodegenerative disease. Because -tubulin acetylation facilitates axonal transport, inhibition of the -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 -tubulin acetylation. Deletion of Sirt2 failed to affect the disease course, but also did not modify -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 -tubulin deacetylase in the nervous system.
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