Display options
Cite
Groh J, Berve K, Martini R. Immune modulation attenuates infantile neuronal ceroid lipofuscinosis in mice before and after disease onset. Brain Commun. 2021;3(2):fcab047doi: 10.1093/braincomms/fcab047.
Groh, J., Berve, K., & Martini, R. (2021). Immune modulation attenuates infantile neuronal ceroid lipofuscinosis in mice before and after disease onset. Brain communications, 3(2), fcab047. https://doi.org/10.1093/braincomms/fcab047
Groh, Janos, et al. "Immune modulation attenuates infantile neuronal ceroid lipofuscinosis in mice before and after disease onset." Brain communications vol. 3,2 (2021): fcab047. doi: https://doi.org/10.1093/braincomms/fcab047
Groh J, Berve K, Martini R. Immune modulation attenuates infantile neuronal ceroid lipofuscinosis in mice before and after disease onset. Brain Commun. 2021 Mar 21;3(2):fcab047. doi: 10.1093/braincomms/fcab047. eCollection 2021. PMID: 33977263; PMCID: PMC8098642.
Copy Download .nbib Format: NLM
Share it on

Brain Commun. 2021 Mar 21;3(2):fcab047. doi: 10.1093/braincomms/fcab047. eCollection 2021.

Immune modulation attenuates infantile neuronal ceroid lipofuscinosis in mice before and after disease onset.

Brain communications

Janos Groh, Kristina Berve, Rudolf Martini

Affiliations

  1. Section of Developmental Neurobiology, Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany.

PMID: 33977263 PMCID: PMC8098642 DOI: 10.1093/braincomms/fcab047

Abstract

Targeting neuroinflammation in models for infantile and juvenile forms of neuronal ceroid lipofuscinosis (NCL, CLN disease) with the clinically established immunomodulators fingolimod and teriflunomide significantly attenuates the neurodegenerative phenotype when applied preventively, i.e. before the development of substantial neural damage and clinical symptoms. Here, we show that in a mouse model for the early onset and rapidly progressing CLN1 form, more complex clinical phenotypes like disturbed motor coordination and impaired visual acuity are also ameliorated by immunomodulation. Moreover, we show that the disease outcome can be attenuated even when fingolimod and teriflunomide treatment starts after disease onset, i.e. when neurodegeneration is ongoing and clinical symptoms are detectable. In detail, treatment with either drug led to a reduction in T-cell numbers and microgliosis in the CNS, although not to the same extent as upon preventive treatment. Pharmacological immunomodulation was accompanied by a reduction of axonal damage, neuron loss and astrogliosis in the retinotectal system and by reduced brain atrophy. Accordingly, the frequency of myoclonic jerks and disturbed motor coordination were attenuated. Overall, disease alleviation was remarkably substantial upon therapeutic treatment with both drugs, although less robust than upon preventive treatment. To test the relevance of putative immune-independent mechanisms of action in this model, we treated CLN1 mice lacking mature T- and B-lymphocytes. Immunodeficient CLN1 mice showed, as previously reported, an improved neurological phenotype in comparison with genuine CLN1 mice which could not be further alleviated by either of the drugs, reflecting a predominantly immune-related therapeutic mechanism of action. The present study supports and strengthens our previous view that repurposing clinically approved immunomodulators may alleviate the course of CLN1 disease in human patients, even though diagnosis usually occurs when symptoms have already emerged.

© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.

Keywords: T-lymphocytes; attenuation of disease; immunomodulation; infantile neuronal ceroid lipofuscinosis; neurodegeneration; neuroinflammation; preventive treatment

References

  1. Mol Ther. 2017 Aug 2;25(8):1889-1899 - PubMed
  2. Doc Ophthalmol. 2003 Jul;107(1):13-36 - PubMed
  3. Neurology. 2019 May 28;92(22):e2538-e2549 - PubMed
  4. N Engl J Med. 2018 Sep 13;379(11):1017-1027 - PubMed
  5. Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13566-71 - PubMed
  6. Sci Rep. 2015 Aug 04;5:12752 - PubMed
  7. Neurobiol Dis. 2017 Dec;108:277-287 - PubMed
  8. Biochim Biophys Acta. 2015 Oct;1852(10 Pt B):2237-41 - PubMed
  9. Neuropharmacology. 2017 May 1;117:149-157 - PubMed
  10. CNS Drugs. 2019 Apr;33(4):315-325 - PubMed
  11. Nature. 1995 Aug 17;376(6541):584-7 - PubMed
  12. J Neuroinflammation. 2018 Jul 3;15(1):194 - PubMed
  13. Hum Mol Genet. 2016 Nov 1;25(21):4686-4702 - PubMed
  14. Drugs. 2014 Apr;74(6):659-74 - PubMed
  15. Mol Genet Metab. 2010 Aug;100(4):349-56 - PubMed
  16. Acta Neuropathol Commun. 2014 May 10;2:54 - PubMed
  17. J Neuroinflammation. 2020 Oct 28;17(1):323 - PubMed
  18. Sci Rep. 2019 Jul 9;9(1):9891 - PubMed
  19. FASEB J. 2019 Apr;33(4):4703-4715 - PubMed
  20. Sci Rep. 2019 Oct 2;9(1):14185 - PubMed
  21. Cell. 1992 Mar 6;68(5):869-77 - PubMed
  22. Lancet Neurol. 2019 Jan;18(1):107-116 - PubMed
  23. J Basic Clin Pharm. 2016 Mar;7(2):27-31 - PubMed
  24. J Neurosci. 2006 Aug 2;26(31):8206-16 - PubMed
  25. Brain. 2013 Apr;136(Pt 4):1083-101 - PubMed
  26. J Vet Intern Med. 2017 Jan;31(1):149-157 - PubMed
  27. Hum Mol Genet. 2015 Sep 1;24(17):4958-70 - PubMed
  28. J Neurosci. 2014 Sep 24;34(39):13077-82 - PubMed
  29. Neurobiol Dis. 2007 Jan;25(1):150-62 - PubMed
  30. Clin Exp Immunol. 2014 Mar;175(3):359-72 - PubMed
  31. J Neurol. 2009 Jan;256(1):89-103 - PubMed
  32. Lancet. 2016 Mar 12;387(10023):1075-1084 - PubMed
  33. Behav Res Methods. 2007 May;39(2):175-91 - PubMed
  34. Exp Neurol. 2009 May;217(1):124-35 - PubMed
  35. Sci Transl Med. 2019 May 1;11(490): - PubMed
  36. Int Immunol. 2008 May;20(5):633-44 - PubMed
  37. Glia. 2016 May;64(5):792-809 - PubMed
  38. Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):14230-5 - PubMed
  39. Brain Dev. 1988;10(2):80-3 - PubMed

Publication Types