Brandt, Trushina, and Bakota

Much More Than a Cytoskeletal Protein: Physiological and Pathological Functions of the Non-microtubule Binding Region of Tau Front. Neurol., 19 October 2020

Tau review article

 

Tau mostly in axons, MAP2 in somatodendritic compartment. Tau ko or inactivation has no major effect in mouse models or cultured nerve cells - likely funciton is to regulate microtubule dynamicity not stability (Qiang L, Sun X, Austin TO, Muralidharan H, Jean DC, Liu M, et al. Tau does not stabilize axonal microtubules but rather enables them to have long labile domains. Curr Biol. (2018) 28:2181–9 e4. doi: 10.1016/j.cub.2018.05.045)

Bioinformatics analysis showed a minimal interactome of 73 direct binding partners (18), and 175 potential new and known tau interacting proteins were recently identified by MALDI-TOF mass spectrometry (19, 19. Sinsky J, Majerova P, Kovac A, Kotlyar M, Jurisica I, Hanes J. Physiological tau interactome in brain and its link to tauopathies. J Proteome Res. (2020) 19:2429–42. doi: 10.1021/acs.jproteome.0c00137). Thus, tau appears to be a multifunctional protein with many interaction partners, and pathological changes in its interactome could contribute significantly to disease development in AD and other tauopathies.

Strong support for a mechanism of action that targets the pathogenic subpopulation of tau

Intrinsically disordered regions highest in N terminal region and proline rich region, increased disorder through vertebrate evolution, MAP2 has no evolutionary trend

MBD

Association of MBD positive lysines with MT negative glutamate electrostatic interactions

Most phosphorylation sites are located in two regions flanking MBD

acetylation of lysines found in MBD neutralizes positive charge

MBD also interacts with heat shock proteins, tau itself, end-binding proteins (EB2), LRP1 (possible involvement in endocytosis)

NTD

aspartate and glutamate = acidic

associated proteins involved in plasma membrane binding and function, exo/endocytosis (annexins, synapsin, synaptotagmin, cynatogyrin) interaction can be phosphorylation dependent, membrane associated tau less phosphorylated than cytosolic tau

also signaling molecules, GSK3beta, 14-3-3 proteins (also PRD, MBD)

PRD

phosphorylation in this domain decreases MT association and PM association

Pathology

move to somatodendritic compartment, enriched in membrane enriched fraction in AD samples