Microtubules Gate Tau Condensation to Spatially Regulate Microtubule Functions

Abstract

Tau is an abundant microtubule-associated protein in neurons. Tau aggregation into insoluble fibrils is a hallmark of Alzheimer's disease and other dementias, yet the physiological state of tau molecules within cells remains unclear. Using single molecule imaging, we directly observe that the microtubule lattice regulates reversible tau selfassociation, leading to dynamic condensation of tau molecules on the microtubule surface. Tau condensates form selectively permissible barriers, spatially regulating the activity of MT severing enzymes and the movement of molecular motors through their boundaries. We propose that reversible self-association of tau molecules, controlled by the microtubule, is an important mechanism of tau's biological functions, and that oligomerization of tau is a common property shared between the physiological and disease forms of the molecule.

Kinesin-1 and dynein use distinct mechanisms to bypass obstacles

“…8 We did not see evidence of motor reversals when DDB encountered an QD obstacle, consistent with recent studies of DDB motility on Tau-coated MTs. 27 However, mobile fraction, velocity and run length of yeast dynein were reduced 30-70% by increasing density of QDs. In comparison to dynein motors, kinesin motility was severely affected by the QDs (Fig.…”

Mitochondria-adaptor TRAK1 promotes kinesin-1 driven transport in crowded environments

“…Knockdown of TRAK1 was demonstrated to result in neurodegeneration, which was suppressed by an additional knockdown of tau 66 . In vitro, tau cooperatively forms cohesive islands on the microtubule surface, preventing kinesin-1 driven transport within the tau island-coated regions of microtubules 52,53 . Our results show that TRAK1 enables KIF5B entering regions covered with tau islands, increasing the probability of KIF5B to traverse tau islands and thus overriding the tau island-dependent blockade of kinesin-1-driven transport.…”

A Combinatorial MAP Code Dictates Polarized Microtubule Transport

“…A large variety of other proteins bind to microtubules, and as such, transport motors must encounter a number of non-enzymatic microtubule-associated proteins (MAPs) that decorate the microtubule cytoskeleton 13 . Disruption of this bidirectional transport system due to mutations in motor complexes or MAPs leads to a wide range of neurodevelopmental and neurodegenerative disorders [13][14][15][16][17] , highlighting the interplay between these classes of proteins.Since the identification of "structural" MAPs that co-purified with polymerized brain tubulin 18 , such as MAP1, MAP2, tau, MAP7, and doublecortin (DCX), MAPs have been described as stabilizers, nucleation-promoting factors, and bundlers of microtubules 19-24 .However, recent work suggests that these MAPs may also function to direct motor transport 6,[25][26][27] . Perhaps the most well-studied MAP with regards to its effects on motors is the Alzheimer's disease-associated MAP, tau, which was originally thought to be axon-specific, but can also be observed in mature dendrites ( Figure S1) 27,28 .…”

“…Tau inhibits kinesin-1 and kinesin-3 to varying degrees 25,26,29-31 , but does not strongly impede processive dynein motility 27 . These differential effects are due to a steric clash between tau and the relatively large kinesin motor domain, which does not exist for the smaller dynein microtubule-binding domain 27,32,33 . MAP2 is localized to dendrites and the axon initial segment and has been shown to inhibit kinesin-1 in vivo 34 .…”

“…However, recent work suggests that these MAPs may also function to direct motor transport 6,[25][26][27] . Perhaps the most well-studied MAP with regards to its effects on motors is the Alzheimer's disease-associated MAP, tau, which was originally thought to be axon-specific, but can also be observed in mature dendrites ( Figure S1) 27,28 . Tau inhibits kinesin-1 and kinesin-3 to varying degrees 25,26,29-31 , but does not strongly impede processive dynein motility 27 .…”