Axon injury triggers EFA-6 mediated destabilization of axonal microtubules via TACC and doublecortin like kinase.
Chen L, Chuang M, Koorman T, Boxem M, Jin Y, Chisholm AD
eLife. 2015 Sep 4;4. doi: 10.7554/eLife.08695.
Axon injury triggers a series of changes in the axonal cytoskeleton that are prerequisites for effective axon regeneration. In Caenorhabditis elegans the signaling protein Exchange Factor for ARF-6 (EFA-6) is a potent intrinsic inhibitor of axon regrowth. Here we show that axon injury triggers rapid EFA-6-dependent inhibition of axonal microtubule (MT) dynamics, concomitant with relocalization of EFA-6. EFA-6 relocalization and axon regrowth inhibition require a conserved 18-aa motif in its otherwise intrinsically disordered N-terminal domain. The EFA-6 N-terminus binds the MT-associated proteins TAC-1/Transforming-Acidic-Coiled-Coil, and ZYG-8/Doublecortin-Like-Kinase, both of which are required for regenerative growth cone formation, and which act downstream of EFA-6. After injury TAC-1 and EFA-6 transiently relocalize to sites marked by the MT minus end binding protein PTRN-1/Patronin. We propose that EFA-6 acts as a bifunctional injury-responsive regulator of axonal MT dynamics, acting at the cell cortex in the steady state and at MT minus ends after injury.
Connecting the dots between tau dysfunction and neurodegeneration.
Frost B, Gotz J, Feany M
Trends in Cell Biology. 2015 Jan;25(1):46-53. doi: 10.1016/j.tcb.2014.07.005. Epub 2014 Aug 26.
Tauopathies are devastating and ultimately fatal neurodegenerative diseases, which are histopathologically defined by insoluble filamentous deposits of abnormally phosphorylated tau protein within neurons and glia. Identifying the causes of abnormal tau phosphorylation and subsequent aggregation has been the focus of much research, and is currently a major target for the development of therapeutic interventions for tauopathies, including Alzheimer’s disease (AD). Much has recently been learned about the sequence of events that lead from tau dysfunction to neuronal death. This review focuses on the cascade of events that are catalyzed by pathological tau, and highlights current and potential therapeutic strategies to target this pathway.