Sex-specific Tau methylation patterns and synaptic transcriptional alterations are associated with neural vulnerability during chronic neuroinflammation. (July 2019)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Journal of autoimmunity. Volume 101(2019)
• Page Start: 56
• Page End: 69
• Publication Date: 2019-07
• Subjects: Multiple sclerosis -- Tau -- Post-translational modifications (PTMs) -- Neuroinflammation -- Lysine methylation; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2019.04.003
• Languages: English
• ISSNs: 0896-8411

Abstract

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. Highlights: Tau exerts a sex-specific protective effects on disease progression in EAE. Lower levels of Tau methylation at lysine K306 are found in mice at chronic EAE stages. Methylation at K306 modulates Tau affinity for microtubules. Downregulation of K306 methylation might represent a homeostatic response to increase axonal stability.