Journal
JOURNAL OF NEUROSCIENCE
Volume 29, Issue 7, Pages 2151-2161Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4660-08.2009
Keywords
BCL-associated anthanogene2; BAG2; heat shock protein 70; Hsp 70; phosphorylated Tau; ubiquitin; proteasome; mir-128a
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Funding
- National Institutes of Health
- Hillblom Foundation
- Everett Fisher Foundation
- National Science Foundation [PHY05-51164]
- Coordenacao de Aperfeic, oamento de Pessoal de Nivel Superior (CAPES) [BEX4494-05-9]
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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.
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