Walter, LM, Koch, CE, Betts, CA, Ahlskog, N, Meijboom, KE, van Westering, TLE, Hazell, G, Bhomra, A, Claus, P, Oster, H, Wood, MJA and Bowerman, M (2018) Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice. Human Molecular Genetics, 27 (20). pp. 3582-3597. ISSN 1460-2083

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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.

Item Type: Article
Additional Information: This is the accepted author manuscript (AAM). The final published version (version of record) is available online via Oxford University Press at Please refer to any applicable terms of use of the publisher.
Subjects: R Medicine > R Medicine (General)
Divisions: Faculty of Medicine and Health Sciences > School of Medicine
Depositing User: Symplectic
Date Deposited: 02 Jul 2018 09:27
Last Modified: 28 Jun 2019 01:30

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