February 2020 Newsletter : MAPping Tau's future

Tau is a structural microtubule-associated protein (MAP) predominantly (but not exclusively) localized to microtubules (MTs) within neuronal axons. Tau is arguably the most studied MAP, primarily due to its central role in neurodegenerative tauopathies (e.g., Alzheimer’s Disease, corticobasal degeneration, frontotemporal dementia)1,2. Importantly, tau is as essential in normal cellular physiology as in neurodegeneration. First described as a MAP which promotes assembly of MTs3-5, tau’s roles now also include MT stabilization, MT bundling, modulation of MT-dependent axonal transport, and regulation of neurite outgrowth1,2,6-10. However, the complete physiological understanding of how tau regulates MT functional organization remains unknown. Four recent studies of novel means by which tau interacts with MTs and other MAPs are discussed below.


Technological advances, especially in microscopy, provide unparalleled direct, single molecule insights into how tau binds MTs9-11. A recent cryo-electron microscopy study12 reveals that tau’s repeat MT binding regions adopt extended structures and bind to the MT surface along a protofilament to stabilize interactions between tubulin heterodimers (Fig. 1). The extended conformation of each repeat region spans intra- and interdimer interfaces, allowing connections between tubulin heterodimers12(Fig. 1). These analyses at the near-atomic level have led some researchers10 to suggest that tau is ideally situated to promote MT assembly, perhaps in the absence of any stabilization given tau’s rapid on-off rate13. Tau’s rate was determined through fast single molecule tracking experiments. These findings contrast with the dogma that structural MAPs adhere to the MT surface in a static fashion to prevent disassembly. In living neuronally-derived cells and primary neurons, tau dynamically binds, dissociates, and binds neighboring MTs rapidly (termed “kiss and hop”) with an on-off rate of 40 milliseconds13. Despite this unexpectedly rapid MT dwell time (shorter by two orders of magnitude than previously reported14), tau was still a potent promoter of tubulin polymerization in neurites. 

Fig. 1. Tau and its multiple roles as a structural MAP. Tau binds in clusters (condensates or islands) on MTs and tubulin oligomers to regulate the binding and activity of motile and non-motile MAPs. Tau binds at the inter-dimer interface via an interaction with tubulin heterodimers which links the dimers. (A) Tau condensates block plus-end directed motility of kinesin-1 and kinesin-3, but not kinesin-8. Kinesin-8 triggers disassembly of the condensates. Minus-end-directed motility of dynein is primarily unimpeded. (B) Tau condensates block the MT severing enzymes spastin and katanin. Green motor, dynein; Blue motors, kinesins.

Although tau is a long-studied structural MAP, novel findings continue to emerge regarding tau-mediated regulation of other MAPs. Recent studies describe novel spatial and functional heterogeneities in tau localized on MTs15-17. Dense islands of bound tau (a.k.a. condensates) assemble in a physiological and reversible manner and distribute along discrete regions of individual MTs to compartmentalize the MT and form selectively MAP-permeable barriers15-17(Fig. 1). Although an earlier paper described tau “patches” on MTs18, Siahaan et al.16 posit that the tau islands are “fundamentally distinct” from these patches. The MT lattice itself regulates physiological self-assembly of tau into condensates/islands in a reversible manner. The condensates form at areas of high MT curvature, are controlled by the nucleotide state of the MT lattice, and rely upon the C-terminal tails of tubulin17. Despite tau’s rapid on-off rate, it regulates the binding and functionality of motile (e.g., plus-end-directed kinesin motors and minus-end-directed dynein motor)18-22 and non-motile MAPs (e.g., MT severing enzymes such as spastin and katanin, MAP6, MAP7)16,17 (Fig. 1). Tau condensates inhibit kinesin motility in an isoform-specific manner and recent single molecule imaging studies15-17 provide additional insights into how tau condensates interact with various MAPs. The condensates/islands halt kinesin-1 and kinesin-3 motility, while kinesin-8 traverses the tau condensates which triggers their disassembly15-17. Similarly, the majority of dynein motors pass through the condensates/islands after a pause16. A shortened, but active form, of the MT severing enzymes spastin and katanin were mostly excluded from condensates, thus protecting the MT from cleavage15-17. Tau expression is inversely related to the expression and function of MAP7 and MAP6. MAP7 competes with tau for the same MT binding sites and can displace the tau condensates/islands15. Also, MAP7 positively regulates kinesin-based cargo transport and kinesin-1 binding to MTs, respectively, in vivo and in vitro15. After MAP7-mediated disruption of bound tau, MAP7 recruits kinesin-1 for binding at MT sites previously occupied by tau15. The two MAPs are not always antagonistic; both MAP7 and tau inhibited kinesin-3 motility15. The relationship between MAP6 and tau is discussed below. Notably, Yuan et al.23 find that changes in tau expression levels (either elevated or reduced) in retinal ganglion cell axons did not affect axonal transport rates in vivo. These seemingly disparate data regarding tau modulation of axonal transport require further analyses, although the “kiss and hop” mechanistic model of tau/MT interactions is compatible with the in vivo results13.


Arguably the most thought-provoking tau results challenge the very dogma that has guided tau research for decades. The majority of tau research, both physiological and pathological, starts with the premise that tau is a stabilizer of MTs under physiological conditions and that upon pathological hyperphosphorylation, tau dissociates from MTs which compromises their stability and results in disassembly1,2,10. Normal axonal MTs consist of labile and stable domains24-26 with tau primarily decorating the former regions10,27. In contrast, MAP6 is predominantly on the stable domains of axonal MTs28,29. Upon depletion of tau in cultured rat neurons, labile MT domains were lost, while the stable domains increased. Furthermore, MAP6’s expression increases and its distribution on axonal MTs expands10,27. Conversely, loss of MAP6 increases the degree of lability in the labile MT domains and results in an increase in tau expression levels and its distribution along axonal MTs10,27. These findings were the basis for the conclusion that tau is in fact not a stabilizer of MTs but instead promotes the assembly of long labile domains and prevents MAP6-mediated stabilization, conferring flexibility to MTs10,27.




Despite tau’s discovery decades ago and its central role in tauopathies, much remains to be discovered about how tau regulates MT structure, function, and binding to other MAPs in healthy and diseased neurons. This dearth of knowledge likely extends beyond tau to other MAPs. To assist researchers in studies of MT and MAP functions and interactions, Cytoskeleton offers tubulin polymerization and binding assay kits, MT live cell imaging probes, purified tubulins, and Signal-Seeker Enrichment kits which allow detection and measurement of endogenous levels of various post-translational modifications – all of which target tubulin and MTs.   


1. Iqbal K. et al. 2016. Tau and neurodegenerative disease: the story so far. Nat. Rev. Neurol. 12, 15-27.

2. Gao Y.-L. et al. 2018. Tau in neurodegenerative disease. Ann. Transl. Med. 6, 175.

3. Weingarten M.D. et al. 1975. A protein factor essential for microtubule assembly. Proc. Natl. Acad. Sci. USA. 72, 1858-1862.

4. Cleveland D.W. et al. 1977a. Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J. Mol. Biol. 116, 207-225.

5. Cleveland D.W. et al. 1977b. Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly. J. Mol. Biol. 116, 227-247.

6. Kanai Y. et al. 1989. Expression of multiple tau isoforms and microtubule bundle formation in fibroblasts transfected with a single tau cDNA. J. Cell Biol. 109, 1173-1184.

7. Scott C.W. et al. 1992. Tau protein induces bundling of microtubules in vitro: comparison of different tau isoforms and a tau protein fragment. J. Neurosci. Res. 33, 19-29.

8. Barlow S. et al. 1994. Stable expression of heterologous microtubule-associated proteins (MAPs) in Chinese hamster ovary cells: evidence for differing roles of MAPs in microtubule organization. J. Cell Biol. 126, 1017-1029.

9. Bodakuntla S. et al. 2019. Microtubule-associated proteins: Structuring the cytoskeleton. Trends Cell Biol. 29, 804-819.

10. Baas P.W. and Qiang L. 2019. Tau: It’s not what you think. Trends. Cell Biol. 29, 452-461.

11. Nogales E. 2016. The development of cryo-EM into a mainstream structural biology technique. Nat. Methods. 13, 24-27.

12. Kellogg E.H. et al. 2018. Near-atomic model of microtubule-tau interactions. Science. 360, 1242-1246.

13. Janning D. et al. 2014. Single-molecule tracking of tau reveals fast kiss-and-hop interaction with microtubules in living neurons. Mol. Biol. Cell. 25, 3541-3551.

14. Konzack S. et al. 2007. Swimming against the tide: mobility of the microtubule-associated protein tau in neurons. J. Neurosci. 27, 9916-9927.

15. Monroy B.Y. et al. 2018. Competition between microtubule-associated proteins directs motor transport. Nat. Commun. 9, 1487.

16. Siahaan V. et al. 2019. Kinetically distinct phases of tau on microtubules regulate kinesin motors and severing enzymes. Nat. Cell Biol. 21, 1086-1092.

17. Tan R. et al. 2019. Microtubules gate tau condensation to spatially regulate microtubule functions. Nat. Cell Biol. 21, 1078-1085.

18. Dixit R. et al. 2008. Differential regulation of dynein and kinesin motor proteins by tau. Science. 319, 1086-1089.

19. Ebneth A. et al. 1998. Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer’s disease. J. Cell Biol. 143, 777-794.

20. Trinczek B. et al. 1999. Tau regulates the attachment/detachment but not the speed of motors in microtubule-dependent transport of single vesicles and organelles. J. Cell Sci. 112, 2355-2367.

21. Seitz A. et al. 2002. Single-molecule investigation of the interference between kinesin, tau and MAP2c. EMBO J. 21, 4896-4905.

22. Vershinin M. et al. 2007. Multiple motor based transport and its regulation by Tau. Proc. Natl. Acad. Sci. USA. 104, 87-92.

23. Yuan A. et al. 2008. Axonal transport rates in vivo are unaffected by tau deletion or overexpression in mice. J. Neurosci. 28, 1682-1687.

24. Baas P.W. and Black M.M. 1990. Individual microtubules in the axon consist of domains that differ in both composition and stability. J. Cell Biol. 111, 495-509.

25. Baas P.W. et al. 1991. Microtubule dynamics in axons and dendrites. J. Neurosci. Res. 30, 134-153.

26. Brown A. et al. 1993. Composite microtubules of the axon: quantitative analysis of tyrosinated and acetylated tubulin along individual axonal microtubules. J. Cell Sci. 104, 339-352.

27. Qiang L. et al. 2018. Tau does not stabilize axonal microtubules but rather enables them to have long labile domains. Curr. Biol. 28, 2181-2189.

28. Slaughter T. and Black M.M. 2003. STOP (stable-tubule-only-polypeptide) is preferentially associated with the stable domain of axonal microtubules. J. Neurocytol. 32, 399-413.

29. Tortosa E. et al. 2017. Dynamic palmitoylation targets MAP6 to the axon to promote microtubule stabilization during neuronal polarization. Neuron. 94, 809-825.

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