A caspase cleaved form of tau is preferentially degraded through the autophagy pathway.
The microtubule-associated protein tau plays a central role in the pathogenesis of Alzheimer disease (AD) and abnormally accumulates as neurofibrillary tangles; therefore, the pathways by which tau is degraded have been examined extensively. In AD brain tau is abnormally truncated at Asp(421) (tauDeltaC), which increases its fibrillogenic properties and results in compromised neuronal function. Given the fact that the accumulation of tauDeltaC is a pathogenic process in AD, in this study we examined whether full-length tau and tauDeltaC are degraded through similar or different mechanisms. To this end a tetracycline-inducible model was used to show that tauDeltaC was degraded significantly faster than full-length tau (FL-tau). Pharmacological inhibition of the proteasome or autophagy pathways demonstrated that although FL-tau is degraded by the proteasome, tauDeltaC is cleared predominantly by macroautophagy. We also found that tauDeltaC binds C terminus of Hsp70-interacting protein more efficiently than tau. This interaction leads to an increased ubiquitylation of tauDeltaC in a reconstituted in vitro assay, but surprisingly, tau (full-length or truncated) was not ubiquitylated in situ. The finding that tauDeltaC and FL-tau are differentially processed by these degradation systems provides important insights for the development of therapeutic strategies, which are focused on modulating degradation systems to preferentially clear pathological forms of the proteins.
Dolan
Philip J
PJ
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Johnson
Gail V W
GV
D000818:Animals; D001343:Autophagy / Q000187:drug effects; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010641:Phenotype; D061988:Proteasome Inhibitors; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism*
D050505:Mutant Proteins; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D016875:tau Proteins; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D020169:Caspases; C078846:epoxomicin
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