The cochaperone BAG2 sweeps paired helical filament- insoluble tau from the microtubule.
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.
Carrettiero
Daniel C
DC
Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, California 93106, USA.
Hernandez
Israel
I
Neveu
Pierre
P
Papagiannakopoulos
Thales
T
Kosik
Kenneth S
KS
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D019556:COS Cells; D002522:Chlorocebus aethiops; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D046911:Macromolecular Substances / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D008870:Microtubules / Q000378:metabolism* / Q000648:ultrastructure; D018832:Molecular Chaperones; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054875:Ubiquitination / Q000235:genetics; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
C492980:BAG2 protein, human; D018840:HSP70 Heat-Shock Proteins; D046911:Macromolecular Substances; D035683:MicroRNAs; D018832:Molecular Chaperones; D016875:tau Proteins; D046988:Proteasome Endopeptidase Complex