Tau‐Induced Traffic Jams Reflect Organelles Accumulation at Points of Microtubule Polar Mismatching

Abstract

It is currently accepted that tau overexpression leads to impaired organelle transport and thus to neuronal degeneration. Nevertheless, the underlying mechanisms that lead to impaired organelle transport are not entirely clear. Using cultured Aplysia neurons and online confocal imaging of human tau, microtubules (MTs), the plus-end tracking protein -end-binding protein 3, retrogradely and anterogradely transported organelles, we found that overexpression of tau generates the hallmarks of human tau pathogenesis. Nevertheless, in contrast to earlier reports, we found that the tau-induced impairment of organelle transport is because of polar reorientation of the MTs along the axon or their displacement to submembrane domains. 'Traffic jams' reflect the accumulation of organelles at points of MT polar discontinuations or polar mismatching rather than because of MT depolymerization. Our findings offer a new mechanistic explanation for earlier observations, which established that tau overexpression leads to impaired retrograde and anterograde organelle transport, while the MT skeleton appeared intact.

Proceedings of the Asia-Pacific Econophysics Conference 2016 — Big Data Analysis and Modeling toward Super Smart Society — (APEC-SSS2016)

“…8 shows for example the growing ends of microtubules in a human cell. Similar observations could be done in cells as different as neurons [38,39] or yeast [40].…”

Intracellular transport driven by cytoskeletal motors: General mechanisms and defects

“…In line with this model, a massive reorientation of the MT network was identified under overexpression of tau in Aplysia neurons [342]. The reorientation might be caused by the elongation of shorter MTs which have been cut by katanin and are brought out of the parallel orientation by steric interaction or molecular motors which pull on the MT fragments.…”

“…[342,343,344] report some experiments in which some mRNA encoding for the plus-end-tracking protein EB3 tagged by GFP is injected in the cell body of cultured Aplysia neurons. EB3-GFP has the property that it binds transiently to dynamically polymerizing MT plus-ends.…”

“…It recently became possible to visualise the dynamics of MTs directly in living neurons using fluorescence and confocal microscopy techniques (see for example Movie S1 in [342]). [342,343,344] report some experiments in which some mRNA encoding for the plus-end-tracking protein EB3 tagged by GFP is injected in the cell body of cultured Aplysia neurons.…”

Deciphering the mechanism underlying late-onset Alzheimer disease

“…24 Such changes might cause the protein extrusion mechanism to decline or fail completely, thereby inducing focal axonal swellings and concomitant accumulation of mitochondria and other organelles ( Figure 1, step 3). 25,26 Disturbed energy metabolism in the axon could induce further tau phosphorylation, 27 an additional neuropathological event that probably facilitates the formation of paired helical filaments (PHFs; precursor elements of neurofibrillary tangles), as seen in doubleimmune-challenged mice. 17 This outcome would lead to further impairments in axonal transport, complete transport blockade, and ultimately axonal leakage ( Figure 1, step 4; Figure 2a).…”