Abstract
The microtubule-binding protein tau has been implicated in the neurofibrillary pathology of Alzheimer's disease. Within affected cells, ubiquitinated and hyperphosphorylated tau assembles into massive filamentous polymers. Eventually these tangle-bearing neurons die. The formation of neurofibrillary tangles closely parallels the progression and anatomic distribution of neuronal loss in Alzheimer's disease, suggesting that these lesions play a role in the disease pathogenesis. Mutations in the human tau gene cause autosomal dominant neurodegenerative disorders. These and other neurodegenerative conditions are also characterized by extensive neurofibrillary pathology. The mechanisms underlying tau-mediated neurotoxicity remain unclear; however, phosphorylated tau is a strong candidate for a toxic molecule, particularly those isoforms phosphorylated by the kinases glycogen synthase kinase 3beta and Cdk5. Here we show that Alzheimer tau binds to Hsc70, and its phosphorylation is a recognition requirement for the addition of ubiquitin (Ub) by the E3 Ub ligase CHIP (carboxyl terminus of the Hsc70-interacting protein) and the E2 conjugating enzyme UbcH5B. Other E3 Ub ligases including parkin and Cbl failed to ubiquitinate phosphorylated tau. CHIP could rescue phosphorylated tau-induced cell death, and therefore the CHIP-Hsc70 complex may provide a new therapeutic target for the tauopathies.
Highlights
Tau inclusions are a major feature of several neurodegenerative diseases including Alzheimer’s disease [1, 2]
Evidence in favor of the Ub-proteasome system involvement in the pathogenesis of neurodegeneration includes the following: 1) inclusion bodies found in a variety of neurodegenerative disorders contain Ub and ubiquitinated proteins; 2) mutations in two Ub pathway enzymes, parkin [11,12,13,14] and ubiquitin carboxyl-terminal hydrolase L1 [15, 16], cause a form of Parkinson’s disease (PD); 3) proteasome activity is decreased or impaired in PD and AD post-mortem brain [17]; 4) a mutation in a multi-Ub gene is associated with AD [18]; and 5) the loss of function of the Ub ligase, Ube3a in SCA1 mice increases neurodegeneration [19]
We showed that phosphorylated tau was ubiquitinated by CHIP complexed to heat shock cognate 70-kDa protein (Hsc70) in collaboration with UbcH5B
Summary
Tau inclusions are a major feature of several neurodegenerative diseases including Alzheimer’s disease [1, 2]. Evidence in favor of the Ub-proteasome system involvement in the pathogenesis of neurodegeneration includes the following: 1) inclusion bodies found in a variety of neurodegenerative disorders contain Ub and ubiquitinated proteins; 2) mutations in two Ub pathway enzymes, parkin [11,12,13,14] and ubiquitin carboxyl-terminal hydrolase L1 [15, 16], cause a form of Parkinson’s disease (PD); 3) proteasome activity is decreased or impaired in PD and AD post-mortem brain [17]; 4) a mutation in a multi-Ub gene is associated with AD [18]; and 5) the loss of function of the Ub ligase, Ube3a in SCA1 mice increases neurodegeneration [19].
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