Dual truncation of tau by caspase-2 accelerates its CHIP-mediated degradation

Intraneuronal aggregates of the microtubule binding protein Tau are a hallmark of different neurodegenerative diseases including Alzheimer's disease (AD). In these aggregates, Tau is modified by posttranslational modifi-cations such as phosphorylation as well as by proteolytic cleavage. Here we identify a novel Tau cleavage site at aspartate 65 (D65) that is specific for caspase-2. In addition, we show that the previously described cleavage site at D421 is also efficiently processed by caspase-2, and both sites are cleaved in human brain samples. Caspase-2-generated Tau fragments show increased aggregation potential in vitro, but do not accumulate in vivo after AAV-mediated overexpression in mouse hippocampus. Interestingly, we observe that steady-state protein levels of caspase-2 generated Tau fragments are low in our in vivo model despite strong RNA expression, suggesting efficient clearance. Consistent with this hypothesis, we find that caspase-2 cleavage significantly improves the recognition of Tau by the ubiquitin E3 ligase CHIP, leading to increased ubiquitination and faster degradation of Tau fragments. Taken together our data thus suggest that CHIP-induced ubiquitination is of particular impor-tance for the clearance of caspase-2 generated Tau fragments in vitro and in vivo.

Automated summary

Intraneuronal aggregates of the microtubule binding protein Tau, which are modified by phosphorylation and proteolytic cleavage, are associated with neurodegenerative diseases such as Alzheimer's disease. This study identifies two caspase-2 cleavage sites on Tau, D65 and D421, and shows that caspase-2-generated Tau fragments have increased aggregation potential in vitro. However, these fragments do not accumulate in vivo, likely due to efficient clearance through ubiquitination and degradation mediated by CHIP. Overall, these findings highlight the importance of CHIP-induced ubiquitination in the clearance of caspase-2 generated Tau fragments.