Advertisement

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

  • Marta Garcia-Miralles
  • Nur Amirah Binte Mohammad Yusof
  • Jing Ying Tan
  • Carola I. Radulescu
  • Harwin Sidik
  • Liang Juin Tan
  • Haim Belinson
  • Neta Zach
  • Michael R. Hayden
  • Mahmoud A. PouladiEmail author
Article

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.

Keywords

Huntington disease Behaviour Laquinimod White matter Oligodendroglia Myelination 

Notes

Acknowledgements

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

Author 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.

Funding Information

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.

Compliance with Ethical Standards

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.

Supplementary material

12035_2018_1393_MOESM1_ESM.pdf (90 kb)
ESM 1 (PDF 89 kb)

References

  1. 1.
    Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, Leavitt BR, Nance M, Ross CA, et al. (2015) Huntington disease. Nat Rev Dis Primers 15005. doi:  https://doi.org/10.1038/nrdp.2015.5
  2. 2.
    Tai YF, Pavese N, Gerhard A, Tabrizi SJ, Barker RA, Brooks DJ, Piccini P (2007) Microglial activation in presymptomatic Huntington’s disease gene carriers. Brain 130:1759–1766.  https://doi.org/10.1093/brain/awm044 CrossRefPubMedGoogle Scholar
  3. 3.
    Andre R, Carty L, Tabrizi SJ (2015) Disruption of immune cell function by mutant huntingtin in Huntington’s disease pathogenesis. Curr Opin Pharmacol 26:33–38.  https://doi.org/10.1016/j.coph.2015.09.008 CrossRefPubMedGoogle Scholar
  4. 4.
    Crotti A, Glass CK (2015) The choreography of neuroinflammation in Huntington’s disease. Trends Immunol 36:364–373.  https://doi.org/10.1016/j.it.2015.04.007 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Denis HL, Lauruol F, Cicchetti F (2018) Are immunotherapies for Huntington’s disease a realistic option? Mol Psychiatry 16:889.  https://doi.org/10.1038/s41380-018-0021-9 CrossRefGoogle Scholar
  6. 6.
    Sapp E, Kegel KB, Aronin N, Hashikawa T, Uchiyama Y, Tohyama K, Bhide PG, Vonsattel JP et al (2001) Early and progressive accumulation of reactive microglia in the Huntington disease brain. J Neuropathol Exp Neurol 60:161–172CrossRefGoogle Scholar
  7. 7.
    Pavese N, Gerhard A, Tai YF, Ho AK, Turkheimer F, Barker RA, Brooks DJ, Piccini P (2006) Microglial activation correlates with severity in Huntington disease: a clinical and PET study. Neurology 66:1638–1643.  https://doi.org/10.1212/01.wnl.0000222734.56412.17 CrossRefPubMedGoogle Scholar
  8. 8.
    Björkqvist M, Wild EJ, Thiele J, Silvestroni A, Andre R, Lahiri N, Raibon E, Lee RV et al (2008) A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease. J Exp Med 205:1869–1877.  https://doi.org/10.1084/jem.20080178 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Politis M, Pavese N, Tai YF, Kiferle L, Mason SL, Brooks DJ, Tabrizi SJ, Barker RA et al (2011) Microglial activation in regions related to cognitive function predicts disease onset in Huntington’s disease: a multimodal imaging study. Hum Brain Mapp 32:258–270.  https://doi.org/10.1002/hbm.21008 CrossRefPubMedGoogle Scholar
  10. 10.
    Politis M, Lahiri N, Niccolini F, Su P, Wu K, Giannetti P, Scahill RI, Turkheimer FE et al (2015) Increased central microglial activation associated with peripheral cytokine levels in premanifest Huntington’s disease gene carriers. Neurobiol Dis 83:115–121.  https://doi.org/10.1016/j.nbd.2015.08.011 CrossRefPubMedGoogle Scholar
  11. 11.
    Wild E, Magnusson A, Lahiri N, Krus U, Orth M, Tabrizi SJ, Björkqvist M (2011) Abnormal peripheral chemokine profile in Huntington’s disease. PLoS Curr 3:RRN1231.  https://doi.org/10.1371/currents.RRN1231 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Weiss A, Träger U, Wild EJ, Grueninger S, Farmer R, Landles C, Scahill RI, Lahiri N et al (2012) Mutant huntingtin fragmentation in immune cells tracks Huntington’s disease progression. J Clin Invest 122:3731–3736.  https://doi.org/10.1172/JCI64565 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Varrin-Doyer M, Zamvil SS, Schulze-Topphoff U (2014) Laquinimod, an up-and-coming immunomodulatory agent for treatment of multiple sclerosis. Exp Neurol 262PA:66–71.  https://doi.org/10.1016/j.expneurol.2014.04.002 CrossRefPubMedCentralGoogle Scholar
  14. 14.
    Kaye J, Piryatinsky V, Birnberg T, Hingaly T, Raymond E, Kashi R, Amit-Romach E, Caballero IS et al (2016) Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor. PNAS 113:E6145–E6152.  https://doi.org/10.1073/pnas.1607843113 CrossRefPubMedGoogle Scholar
  15. 15.
    Aharoni R, Saada R, Eilam R, Hayardeny L, Sela M, Arnon R (2012) Oral treatment with laquinimod augments regulatory T-cells and brain-derived neurotrophic factor expression and reduces injury in the CNS of mice with experimental autoimmune encephalomyelitis. J Neuroimmunol 251:14–24.  https://doi.org/10.1016/j.jneuroim.2012.06.005 CrossRefPubMedGoogle Scholar
  16. 16.
    Thöne J, Ellrichmann G, Seubert S, Peruga I, Lee DH, Conrad R, Hayardeny L, Comi G et al (2012) Modulation of autoimmune demyelination by laquinimod via induction of brain-derived neurotrophic factor. Am J Pathol 180:267–274.  https://doi.org/10.1016/j.ajpath.2011.09.037 CrossRefPubMedGoogle Scholar
  17. 17.
    Garcia-Miralles M, Hong X, Tan LJ, Caron NS, Huang Y, To XV, Lin RY, Franciosi S et al (2016) Laquinimod rescues striatal, cortical and white matter pathology and results in modest behavioural improvements in the YAC128 model of Huntington disease. Sci Rep 6:31652.  https://doi.org/10.1038/srep31652 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Garcia-Miralles M, Geva M, Tan JY, Yusof NABM, Cha Y, Kusko R, Tan LJ, Xu X et al (2017) Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice. JCI Insight 2.  https://doi.org/10.1172/jci.insight.95665
  19. 19.
    Brooks SP, Dunnett SB (2009) Tests to assess motor phenotype in mice: a user’s guide. Nat Rev Neurosci 10:519–529.  https://doi.org/10.1038/nrn2652 CrossRefPubMedGoogle Scholar
  20. 20.
    Pouladi MA, Graham RK, Karasinska JM, Xie Y, Santos RD, Petersen A, Hayden MR (2009) Prevention of depressive behaviour in the YAC128 mouse model of Huntington disease by mutation at residue 586 of huntingtin. Brain 132:919–932.  https://doi.org/10.1093/brain/awp006 CrossRefPubMedGoogle Scholar
  21. 21.
    Paxinos G, Franklin KB (2012) Paxinos and franklin's the mouse brain in stereotaxic coordinates. Academic PressGoogle Scholar
  22. 22.
    Barazany D, Basser PJ, Assaf Y (2009) In vivo measurement of axon diameter distribution in the corpus callosum of rat brain. Brain 132(5):1210–1220CrossRefGoogle Scholar
  23. 23.
    Pouladi MA, Stanek LM, Xie Y, Franciosi S, Southwell AL, Deng Y, Butland S, Zhang W et al (2012) Marked differences in neurochemistry and aggregates despite similar behavioural and neuropathological features of Huntington disease in the full-length BACHD and YAC128 mice. Hum Mol Genet 21:2219–2232.  https://doi.org/10.1093/hmg/dds037 CrossRefPubMedGoogle Scholar
  24. 24.
    Van Raamsdonk JM, Murphy Z, Slow EJ, Leavitt BR, Hayden MR (2005) Selective degeneration and nuclear localization of mutant huntingtin in the YAC128 mouse model of Huntington disease. Hum Mol Genet 14:3823–3835.  https://doi.org/10.1093/hmg/ddi407 CrossRefPubMedGoogle Scholar
  25. 25.
    Van Raamsdonk JM, Pearson J, Slow EJ, Hossain SM, Leavitt BR, Hayden MR et al (2005) Cognitive dysfunction precedes neuropathology and motor abnormalities in the YAC128 mouse model of Huntington’s disease. J Neurosci 25:4169–4180.  https://doi.org/10.1523/JNEUROSCI.0590-05.2005 CrossRefPubMedGoogle Scholar
  26. 26.
    Carroll JB, Lerch JP, Franciosi S, Spreeuw A, Bissada N, Henkelman RM, Hayden MR (2011) Natural history of disease in the YAC128 mouse reveals a discrete signature of pathology in Huntington disease. Neurobiol Dis 43:257–265.  https://doi.org/10.1016/j.nbd.2011.03.018 CrossRefPubMedGoogle Scholar
  27. 27.
    Teo RTY, Hong X, Yu-Taeger L, Huang Y, Tan LJ, Xie Y, To XV, Guo L et al (2016) Structural and molecular myelination deficits occur prior to neuronal loss in the YAC128 and BACHD models of Huntington disease. Hum Mol Genet 25:2621–2632.  https://doi.org/10.1093/hmg/ddw122 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Brück W, Pförtner R, Pham T, Zhang J, Hayardeny L, Piryatinsky V et al. (2012) Reduced astrocytic NF-κB activation by laquinimod protects from cuprizone-induced demyelination. Acta Neuropathologica 124(3):411–424.  https://doi.org/10.1007/s00401-012-1009-1 CrossRefGoogle Scholar
  29. 29.
    Zwilling D, Huang S-Y, Sathyasaikumar KV, Notarangelo FM, Guidetti P, Wu HQ, Lee J, Truong J et al (2011) Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell 145:863–874.  https://doi.org/10.1016/j.cell.2011.05.020 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Ehrnhoefer DE, Caron NS, Deng Y, Qiu X, Tsang M, Hayden MR (2016) Laquinimod decreases Bax expression and reduces caspase-6 activation in neurons. Exp Neurol 283:121–128.  https://doi.org/10.1016/j.expneurol.2016.06.008 CrossRefPubMedGoogle Scholar
  31. 31.
    Xiang Z, Valenza M, Cui L, Leoni V, Jeong HK, Brilli E, Zhang J, Peng Q et al (2011) Peroxisome-proliferator-activated receptor gamma coactivator 1 α contributes to dysmyelination in experimental models of Huntington’s disease. J Neurosci 31:9544–9553.  https://doi.org/10.1523/JNEUROSCI.1291-11.2011 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Jin J, Peng Q, Hou Z, Jiang M, Wang X, Langseth AJ, Tao M, Barker PB et al (2015) Early white matter abnormalities, progressive brain pathology and motor deficits in a novel knock-in mouse model of Huntington’s disease. Hum Mol Genet 24:2508–2527.  https://doi.org/10.1093/hmg/ddv016 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Baumann N, Pham-Dinh D (2001) Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 81:871–927CrossRefGoogle Scholar
  34. 34.
    Jahn O, Tenzer S, Werner HB (2009) Myelin proteomics: molecular anatomy of an insulating sheath. Mol Neurobiol 40:55–72.  https://doi.org/10.1007/s12035-009-8071-2 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Shackleford G, Sampathkumar NK, Hichor M et al (2018) Involvement of Aryl hydrocarbon receptor in myelination and in human nerve sheath tumorigenesis. PNAS 115:E1319–E1328.  https://doi.org/10.1073/pnas.1715999115 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Marta Garcia-Miralles
    • 1
  • Nur Amirah Binte Mohammad Yusof
    • 1
  • Jing Ying Tan
    • 1
  • Carola I. Radulescu
    • 1
  • Harwin Sidik
    • 1
  • Liang Juin Tan
    • 1
  • Haim Belinson
    • 2
  • Neta Zach
    • 2
  • Michael R. Hayden
    • 1
    • 2
    • 3
    • 4
  • Mahmoud A. Pouladi
    • 1
    • 4
    Email author
  1. 1.Translational Laboratory in Genetic MedicineAgency for Science, Technology and Research, Singapore (A*STAR)SingaporeSingapore
  2. 2.Teva Pharmaceutical Industries Ltd, Research and DevelopmentNetanyaIsrael
  3. 3.Centre for Molecular Medicine and Therapeutics, Child and Family Research InstituteUniversity of British ColumbiaVancouverCanada
  4. 4.Department of Medicine, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore

Personalised recommendations