Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice

Walter, Lisa M; Koch, Christiane E; Betts, Corinne A; Ahlskog, Nina; Meijboom, Katharina E; van Westering, Tirsa L E; Hazell, Gareth; Bhomra, Amarjit; Claus, Peter; Oster, Henrik; Wood, Matthew J A; Bowerman, Melissa

doi:10.1093/hmg/ddy249

Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice

Walter, Lisa M; Koch, Christiane E; Betts, Corinne A; Ahlskog, Nina; Meijboom, Katharina E; van Westering, Tirsa L E; Hazell, Gareth; Bhomra, Amarjit; Claus, Peter; Oster, Henrik; Wood, Matthew J A; Bowerman, Melissa

Authors

Lisa M Walter

Christiane E Koch

Corinne A Betts

Nina Ahlskog

Katharina E Meijboom

Tirsa L E van Westering

Gareth Hazell

Amarjit Bhomra

Peter Claus

Henrik Oster

Matthew J A Wood

Melissa Bowerman m.bowerman@keele.ac.uk

Abstract

Physiology and behaviour are critically dependent on circadian regulation via a core set of clock genes, dysregulation of which leads to metabolic and sleep disturbances. Metabolic and sleep perturbations occur in spinal muscular atrophy (SMA), a neuromuscular disorder caused by loss of the survival motor neuron (SMN) protein and characterised by motor neuron loss and muscle atrophy. We therefore investigated the expression of circadian rhythm genes in various metabolic tissues and spinal cord of the Taiwanese Smn-/-;SMN2 SMA animal model. We demonstrate a dysregulated expression of the core clock genes (clock, ARNTL/Bmal1, Cry1/2, Per1/2) and clock output genes (Nr1d1 and Dbp) in SMA tissues during disease progression. We also uncover an age- and tissue-dependent diurnal expression of the Smn gene. Importantly, we observe molecular and phenotypic corrections in SMA mice following direct light modulation. Our study identifies for a key relationship between a SMA pathology and peripheral core clock gene dysregulation, highlights the influence of SMN on peripheral circadian regulation and metabolism and has significant implications for the development of peripheral therapeutic approaches and clinical care management of SMA patients.

Journal Article Type	Article
Acceptance Date	Jun 28, 2018
Online Publication Date	Aug 14, 2018
Publication Date	Oct 15, 2018
Publicly Available Date	May 26, 2023
Journal	Human Molecular Genetics
Print ISSN	1460-2083
Electronic ISSN	1460-2083
Publisher	Oxford University Press
Peer Reviewed	Peer Reviewed
Volume	27
Issue	20
Pages	3582-3597
DOI	https://doi.org/10.1093/hmg/ddy249
Publisher URL	https://academic.oup.com/hmg/article/27/20/3582/5048949