Tau-ism: The Yin and Yang of Microtubule Sliding, Detachment, and Rupture

Traumatic brain injury is a nondege-nerative, noncongenital insult to thebrain caused by external mechanicalforces. Recent studies suggest thateven mild concussions—if repeti-tive—can trigger progressive neuro-logical degeneration, a condition thatis now widely known as ‘‘chronic trau-matic encephalopathy’’ (1). Notably,chronic traumatic encephalopathycon-tinues to progress even decades afterthe initial insult; the more severe theoriginal injury and the longer thesurvival, the greater the severity ofneurodegeneration. Progressive axonaldamage and structural degradationare classic hallmarks of chronic trau-matic encephalopathy. Strikingly,these symptoms appear to be sharedby a number of other neurodegenera-tive diseases including Alzheimer’sdisease and Parkinsonism. However,the molecular mechanisms of axonalfailure remain poorly understood.One of the most common patholog-ical features of traumatic brain injuryis diffuse axonal injury (2). To date,the only method to reliably diagnosediffuse axonal injury is post mortemhistopathology, where it manifests it-self through extensive damage inwhite-matter tissue. More than half acentury ago, experiments with gelatinmolds have established that patholog-ical white-matter damage is a directconsequence of elevated mechanicalstrains and strain rates (3): At lowstrain rates, axons that make upwhite-matter tissue are highly com-pliant and ductile; they can easilydeform and revert to their initialconformation. At high strain rates,axons stiffen and become brittle; theyare vulnerable to mechanical failure(Fig. 1). Axonal failure manifests itselfin two modes, primary axotomy,the immediate, complete mechanicalrupture, and secondary axotomy, theprogressive degradation and gradualfailure (1). Although secondary axot-omy is by far the more common failuremode, the precise sequence of eventsby which the axonal cytoskeleton de-grades is unknown.The axonal cytoskeleton is made upof microtubules, neuroﬁlaments, andmicroﬁlaments. Neuronal microtu-bules are structurally similar to micro-tubules in all other cells of our body:Composed of heterodimers of a- andb-tubulin that form 13 laterally joinedprotoﬁlaments, microtubules are hol-low tubes with a diameter of 24 nm.With a high resistance to bending anda stiffness of 2.0 GPa, microtubulesareundoubtedlythestrongestcytoskel-etal ﬁlaments in eukaryotic cells. Assuch, they play a unique role in a num-ber of cellular processes, maintainingstructural stability and providinghighways for intracellular transport.While the microtubule ultrastructureissimilarinall eukaryoticcells,micro-tubule organization in neurons differssigniﬁcantly from nonneuronal cells(4): Axons can extend up to a meterin length and their microtubules neverrun continuously from the cell bodyto the distal end. Instead, they formbundles of microtubule segments with10–20 microtubules in any given crosssection. Neuronal microtubules arenucleated at the centrosome withinthe cell body, then rapidly released,and delivered into the axon via molec-ular motors.Duringtransport,microtu-bules shorten to provide subunits forthe elongation of other microtubules.This explains why the microtubulelength can vary signiﬁcantly along theaxon, with up to 100 mm and longertoward the cell body and 2 mm andshorter toward the distal end (3). Indi-vidual microtubules are stabilized andcross-linked to form the axonal cyto-skeleton via microtubule-associatedproteins.The most prominent microtubule-associated protein, tau, was discoveredmore than four decades ago (5). Adecade later, tau took center stage asthe major component of neuroﬁbrillarytangles, which are now widely knownas the primary markers of Alzheimer’sdisease (6). Tau is primarily a neuronalprotein.Intheadulthumanbrain,alter-native mRNA splicing generates sixmajor isoforms of tau varying from352 to 441 amino acids in length. Allisoforms share three common do-mains: a microtubule-binding domaincomposed of repeats of an evolution-arily conserved tubulin binding motif,a positively charged proline-rich re-gion, and a negatively charged N-ter-minus (7). The six isoforms differ bythe number of microtubule-binding re-peats, either three or four, and by thepresence or absence of one or twoN-terminal inserts. Tau is nativelydisordered. By binding to microtu-bules, tau becomes more organizedand contributes directly or indirectlyto key structural and regulatorycellular function. Within individualmicrotubules, tau modulates microtu-bule polymerization, controls microtu-bule structure, and regulates axonaltransport; the tubulin-binding repeatsof tau bind to hydrophobic pocketsbetween the a- and b-tubulin hetero-dimers of a microtubule to stabilizeits straight protoﬁlament conforma-tion (8). Within the axonal cytoskel-eton, tau promotes the assembly ofindividual microtubules into well-organized, evenly spaced bundles;two tau proteins of neighboring micro-tubules form an electrostatic zipper