Hdac6 deletion delays disease progression in the SOD1G93A mouse model of ALS.
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.
Experimental Neurology, Department of Neurosciences, Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven (KU Leuven), Leuven, Belgium.
Ines
I
Taes
Mieke
M
Timmers
Nicole
N
Hersmus
André
A
Bento-Abreu
Ludo
L
Van Den Bosch
Philip
P
Van Damme
Johan
J
Auwerx
Wim
W
Robberecht
D000107:Acetylation; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001370:Axonal Transport / Q000235:genetics; D001369:Axons / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D056565:Sirtuin 2 / Q000235:genetics* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
D014404:Tubulin; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases