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The Journal of Neuroscience, February 18, 2009, 29(7):2151-2161; doi:10.1523/JNEUROSCI.4660-08.2009

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Neurobiology of Disease
The Cochaperone BAG2 Sweeps Paired Helical Filament- Insoluble Tau from the Microtubule

Daniel C. Carrettiero,^1,3 * Israel Hernandez,^1 * Pierre Neveu,^1,2 Thales Papagiannakopoulos,¹ and Kenneth S. Kosik¹

¹Neuroscience Research Institute, and ²Kavli Institute for Theoretical Physics, University of California Santa Barbara, Santa Barbara, California 93106, and ³Biosciences Institute, Department of Physiology, University of Sao Paulo, 05508-090, Sao Paulo, Brazil

Correspondence should be addressed to Kenneth S. Kosik at the above address. Email: kosik{at}lifesci.ucsb.edu

Tau inclusions are a prominent feature of many neurodegenerative diseases including Alzheimer's disease. Their accumulation in neurons as ubiquitinated filaments suggests a failure in the degradation limb of the Tau pathway. The components of a Tau protein triage system consisting of CHIP/Hsp70 and other chaperones have begun to emerge. However, the site of triage and the master regulatory elements are unknown. Here, we report an elegant mechanism of Tau degradation involving the cochaperone BAG2. The BAG2/Hsp70 complex is tethered to the microtubule and this complex can capture and deliver Tau to the proteasome for ubiquitin-independent degradation. This complex preferentially degrades Sarkosyl insoluble Tau and phosphorylated Tau. BAG2 levels in cells are under the physiological control of the microRNA miR-128a, which can tune paired helical filament Tau levels in neurons. Thus, we propose that ubiquitinated Tau inclusions arise due to shunting of Tau degradation toward a less efficient ubiquitin-dependent pathway.

Key words: BCL-associated anthanogene2; BAG2; heat shock protein 70; Hsp 70; phosphorylated Tau; ubiquitin; proteasome; mir-128a

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Received Sept. 29, 2008; accepted Dec. 11, 2008.

Correspondence should be addressed to Kenneth S. Kosik at the above address. Email: kosik{at}lifesci.ucsb.edu

This article has been cited by other articles:

				U. K. Jinwal, Y. Miyata, J. Koren III, J. R. Jones, J. H. Trotter, L. Chang, J. O'Leary, D. Morgan, D. C. Lee, C. L. Shults, et al. Chemical Manipulation of Hsp70 ATPase Activity Regulates Tau Stability J. Neurosci., September 30, 2009; 29(39): 12079 - 12088. [Abstract] [Full Text] [PDF]

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