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Lookup NU author(s): Dr Luciano Saieva
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Proximal spinal muscular atrophy (SMA) is a childhood-onset degenerative disease resulting from the selective loss of motor neurons in the spinal cord. SMA is caused by the loss of SMN1 (survival motor neuron 1) but retention of SMN2. The number of copies of SMN2 modifies disease severity in SMA patients as well as in mouse models, making SMN2 a target for therapeutics development. Sodium butyrate (BA) and its analog (4PBA) have been shown to increase SMN2 expression in SMA cultured cells. In this study, we examined the effects of BA, 4PBA as well as two BA prodrugs glyceryl tributyrate (BA3G) and VX563-on the phenotype of SMN Delta 7 SMA mice. Treatment with 4PBA, BA3G and VX563 but not BA beginning at PND04 significantly improved the lifespan and delayed disease end stage, with administration of VX563 also improving the growth rate of these mice. 4PBA and VX563 improved the motor phenotype of SMN Delta 7 SMA mice and prevented spinal motor neuron loss. Interestingly, neither 4PBA nor VX563 had an effect on SMN expression in the spinal cords of treated SMN Delta 7 SMA mice; however, they inhibited histone deacetylase (HDAC) activity and restored the normal phosphorylation states of Akt and glycogen synthase kinase 3 beta, both of which are altered by SMN deficiency in vivo. These observations show that BA-based compounds with favorable pharmacokinetics ameliorate SMA pathology possibly by modulating HDAC and Akt signaling. (C) 2016 Elsevier Inc. All rights reserved.
Author(s): Butchbach MER, Lumpkin CJ, Harris AW, Saieva L, Edwards JD, Workman E, Simard LR, Pellizzoni L, Burghes AHM
Publication type: Article
Publication status: Published
Journal: Experimental Neurology
Year: 2016
Volume: 279
Pages: 13-26
Print publication date: 01/05/2016
Online publication date: 15/02/2016
Acceptance date: 13/02/2016
ISSN (print): 0014-4886
ISSN (electronic): 1090-2430
Publisher: Academic Press
URL: http://dx.doi.org/10.1016/j.expneurol.2016.02.009
DOI: 10.1016/j.expneurol.2016.02.009
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