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Laquinimod Treatment Improves Myelination Deficits at the Transcriptional and Ultrastructural Levels in the YAC128 Mouse Model of Huntington Disease

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Abstract

Laquinimod, an immunomodulatory agent under clinical development for Huntington disease (HD), has recently been shown to confer behavioural improvements that are coupled with prevention of atrophy of the white matter (WM)-rich corpus callosum (CC) in the YAC128 HD mice. However, the nature of the WM improvements is not known yet. Here we investigated the effects of laquinimod on HD-related myelination deficits at the cellular, molecular and ultrastructural levels. We showed that laquinimod treatment improves motor learning and motor function deficits in YAC128 HD mice, and confirmed its antidepressant effect even at the lowest dose used. In addition, we demonstrated for the first time the beneficial effects of laquinimod on myelination in the posterior region of the CC where it reversed changes in myelin sheath thickness and rescued Mbp mRNA and protein deficits. Furthermore, the effect of laquinimod on myelin-related gene expression was not region-specific since the levels of the Mbp and Plp1 transcripts were also increased in the striatum. Also, we did not detect changes in immune cell densities or levels of inflammatory genes in 3-month-old YAC128 HD mice, and these were not altered with laquinimod treatment. Thus, the beneficial effects of laquinimod on HD-related myelination abnormalities in YAC128 HD mice do not appear to be dependent on its immunomodulatory activity. Altogether, our findings describe the beneficial effects of laquinimod treatment on HD-related myelination abnormalities and highlight its therapeutic potential for the treatment of WM pathology in HD patients.

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Acknowledgements

Microscopy images for this study were acquired at the SBIC-Nikon Imaging Centre (Biopolis, Singapore).

Funding

This study was supported by a grant from Teva Pharmaceuticals. M.A.P. is supported by a Strategic Positioning Fund for Genetic Orphan Diseases (SPF2012/005) from the Agency for Science Technology and Research, and by the National University of Singapore, Singapore.

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Authors and Affiliations

  1. Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore, 138648, Singapore

    Marta Garcia-Miralles, Nur Amirah Binte Mohammad Yusof, Jing Ying Tan, Carola I. Radulescu, Harwin Sidik, Liang Juin Tan, Michael R. Hayden & Mahmoud A. Pouladi

  2. Teva Pharmaceutical Industries Ltd, Research and Development, Netanya, Israel

    Haim Belinson, Neta Zach & Michael R. Hayden

  3. Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada

    Michael R. Hayden

  4. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore

    Michael R. Hayden & Mahmoud A. Pouladi

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  1. Marta Garcia-Miralles
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Contributions

M.G.M. designed and performed experiments, data analysis and interpretation, and wrote the manuscript. N.A.B.M.Y., J.Y.T., C.R., H.S. and L.J.T. performed experiments. N.Z. and M.R.H. contributed to the study design and revision of the manuscript. M.A.P. conceived and designed experiments, participated in analysis and interpretation of data, and wrote the manuscript.

Corresponding author

Correspondence to Mahmoud A. Pouladi.

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Conflict of Interest

N.Z., H.B. and M.R.H. are employees of Teva Pharmaceuticals, and contributed to the study design and revision of the manuscript. Teva Pharmaceuticals played no role in the treatment or testing of animals, or the collection, analysis and interpretation of the results.

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Garcia-Miralles, M., Yusof, N.A.B.M., Tan, J.Y. et al. Laquinimod Treatment Improves Myelination Deficits at the Transcriptional and Ultrastructural Levels in the YAC128 Mouse Model of Huntington Disease. Mol Neurobiol 56, 4464–4478 (2019). https://doi.org/10.1007/s12035-018-1393-1

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