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Protective effects of butyrate-based compounds on a mouse model for spinal muscular atrophy

Lookup NU author(s): Dr Luciano Saieva

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Abstract

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.


Publication metadata

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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Funding

Funder referenceFunder name
Cure SMA
Miracles for Madison Fund
Nemours Foundation
P20GM103464National Institute of General Medical Sciences of the National Institutes of Health
R01NS069601National Institute of Neurological Disorders and Stroke of the National Institutes of Health
R01NS38650National Institute of Neurological Disorders and Stroke of the National Institutes of Health

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