Sex-specific Tau methylation patterns and synaptic transcriptional alterations are associated with neural vulnerability during chronic neuroinflammation

Alessandro Didonna, Ester Cantó, Hengameh Shams, Noriko Isobe, Chao Zhao, Stacy J. Caillier, Carlo Condello, Hana Yamate-Morgan, Seema K. Tiwari-Woodruff, Mohammad R.K. Mofrad, Stephen L. Hauser, Jorge R. Oksenberg

Research output: Contribution to journalArticle

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Abstract

The molecular events underlying the transition from initial inflammatory flares to the progressive phase of multiple sclerosis (MS) remain poorly understood. Here, we report that the microtubule-associated protein (MAP) Tau exerts a gender-specific protective function on disease progression in the MS model experimental autoimmune encephalomyelitis (EAE). A detailed investigation of the autoimmune response in Tau-deficient mice excluded a strong immunoregulatory role for Tau, suggesting that its beneficial effects are presumably exerted within the central nervous system (CNS). Spinal cord transcriptomic data show increased synaptic dysfunctions and alterations in the NF-kB activation pathway upon EAE in Tau-deficient mice as compared to wildtype animals. We also performed the first comprehensive characterization of Tau post-translational modifications (PTMs) in the nervous system upon EAE. We report that the methylation levels of the conserved lysine residue K306 are significantly decreased in the chronic phase of the disease. By combining biochemical assays and molecular dynamics (MD) simulations, we demonstrate that methylation at K306 decreases the affinity of Tau for the microtubule network. Thus, the down-regulation of this PTM might represent a homeostatic response to enhance axonal stability against an autoimmune CNS insult. The results, altogether, position Tau as key mediator between the inflammatory processes and neurodegeneration that seems to unify many CNS diseases.

Original languageEnglish
Pages (from-to)56-69
Number of pages14
JournalJournal of Autoimmunity
Volume101
DOIs
Publication statusPublished - Jul 1 2019

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Autoimmune Experimental Encephalomyelitis
Methylation
Post Translational Protein Processing
Multiple Sclerosis
Central Nervous System
Microtubule-Associated Proteins
NF-kappa B
Central Nervous System Diseases
Molecular Dynamics Simulation
Autoimmunity
Microtubules
Nervous System
Lysine
Disease Progression
Spinal Cord
Chronic Disease
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Sex-specific Tau methylation patterns and synaptic transcriptional alterations are associated with neural vulnerability during chronic neuroinflammation. / Didonna, Alessandro; Cantó, Ester; Shams, Hengameh; Isobe, Noriko; Zhao, Chao; Caillier, Stacy J.; Condello, Carlo; Yamate-Morgan, Hana; Tiwari-Woodruff, Seema K.; Mofrad, Mohammad R.K.; Hauser, Stephen L.; Oksenberg, Jorge R.

In: Journal of Autoimmunity, Vol. 101, 01.07.2019, p. 56-69.

Research output: Contribution to journalArticle

Didonna, A, Cantó, E, Shams, H, Isobe, N, Zhao, C, Caillier, SJ, Condello, C, Yamate-Morgan, H, Tiwari-Woodruff, SK, Mofrad, MRK, Hauser, SL & Oksenberg, JR 2019, 'Sex-specific Tau methylation patterns and synaptic transcriptional alterations are associated with neural vulnerability during chronic neuroinflammation', Journal of Autoimmunity, vol. 101, pp. 56-69. https://doi.org/10.1016/j.jaut.2019.04.003
Didonna, Alessandro ; Cantó, Ester ; Shams, Hengameh ; Isobe, Noriko ; Zhao, Chao ; Caillier, Stacy J. ; Condello, Carlo ; Yamate-Morgan, Hana ; Tiwari-Woodruff, Seema K. ; Mofrad, Mohammad R.K. ; Hauser, Stephen L. ; Oksenberg, Jorge R. / Sex-specific Tau methylation patterns and synaptic transcriptional alterations are associated with neural vulnerability during chronic neuroinflammation. In: Journal of Autoimmunity. 2019 ; Vol. 101. pp. 56-69.
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