Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model

• Published in: Scientific reports Vol. 10; no. 1; p. 13482
• Main Authors: Chi, Hao, Sun, Lee, Shiu, Ren-Huei, Han, Rui, Hsieh, Chien-Ping, Wei, Tzu-Min, Lo, Chung-Chuan, Chang, Hui-Yun, Sang, Tzu-Kang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.08.2020; Nature Publishing Group
• Subjects: 631/208; 631/378; 692/420; 692/699; Actin; Alzheimer Disease - metabolism; Alzheimer's disease; Animals; Axons - metabolism; Cytotoxicity; Disease Models, Animal; Drosophila; Female; Humanities and Social Sciences; Humans; Kinases; Localization; Male; multidisciplinary; Mutation; Neurodegeneration; Neurodegenerative diseases; Neurofibrillary tangles; Neurofibrillary Tangles - metabolism; Neurons - metabolism; Pathology; Phosphorylation; Phosphorylation - genetics; Protein Processing, Post-Translational; Proteolysis; Science; Science (multidisciplinary); Spheroids; Tau protein; tau Proteins - genetics; tau Proteins - metabolism; Tauopathies - metabolism; Therapeutic applications
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-70423-1

Hyperphosphorylated and truncated tau variants are enriched in neuropathological aggregates in diseases known as tauopathies. However, whether the interaction of these posttranslational modifications affects tau toxicity as a whole remains unresolved. By expressing human tau with disease-related Ser/Thr residues to simulate hyperphosphorylation, we show that despite severe neurodegeneration in full-length tau, with the truncation at Asp421, the toxicity is ameliorated. Cytological and biochemical analyses reveal that hyperphosphorylated full-length tau distributes in the soma, the axon, and the axonal terminal without evident distinction, whereas the Asp421-truncated version is mostly restricted from the axonal terminal. This discrepancy is correlated with the fact that fly expressing hyperphosphorylated full-length tau, but not Asp421-cleaved one, develops axonopathy lesions, including axonal spheroids and aberrant actin accumulations. The reduced presence of hyperphosphorylated tau in the axonal terminal is corroborated with the observation that flies expressing Asp421-truncated variants showed less motor deficit, suggesting synaptic function is preserved. The Asp421 cleavage of tau is a proteolytic product commonly found in the neurofibrillary tangles. Our finding suggests the coordination of different posttranslational modifications on tau may have an unexpected impact on the protein subcellular localization and cytotoxicity, which may be valuable when considering tau for therapeutic purposes.