NDLI: A Caspase Cleaved Form of Tau Is Preferentially Degraded through the Autophagy Pathway*

Content Provider	PubMed Central
Author	Dolan, Philip J. Johnson, Gail V. W.
Abstract	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 Asp421 (tauΔC), which increases its fibrillogenic properties and results in compromised neuronal function. Given the fact that the accumulation of tauΔC is a pathogenic process in AD, in this study we examined whether full-length tau and tauΔC are degraded through similar or different mechanisms. To this end a tetracycline-inducible model was used to show that tauΔC 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, tauΔC is cleared predominantly by macroautophagy. We also found that tauΔC binds C terminus of Hsp70-interacting protein more efficiently than tau. This interaction leads to an increased ubiquitylation of tauΔC in a reconstituted in vitro assay, but surprisingly, tau (full-length or truncated) was not ubiquitylated in situ. The finding that tauΔC 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.
Related Links	http://dx.doi.org/10.1074/jbc.m110.110940
Ending Page	21987
Page Count	10
Starting Page	21978
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	29
Volume Number	285
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2010-07-16
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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