Ca2+/calmodulin-dependent protein kinase II promotes neurodegeneration caused by tau phosphorylated at Ser262/356 in a transgenic Drosophila model of tauopathy

• Published in: Journal of biochemistry (Tokyo) Vol. 162; no. 5; pp. 335 - 342
• Main Authors: Oka, Mikiko, Fujisaki, Naoki, Maruko-Otake, Akiko, Ohtake, Yosuke, Shimizu, Sawako, Saito, Taro, Hisanaga, Shin-Ichi, Iijima, Koichi M, Ando, Kanae
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.11.2017
• Subjects: Amino Acid Sequence; Animals; Animals, Genetically Modified; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Cytosol; Drosophila melanogaster - genetics; Female; Microtubules - physiology; Nerve Degeneration - genetics; Nerve Degeneration - metabolism; Phosphorylation; Protein Transport; Regular Papers; tau Proteins - metabolism; tauopathy; Ca2+/calmodulin (CaM)-dependent protein kinase II; microtubule-associated protein tau; phosphorylation; Drosophila
• ISSN: 0021-924X; 1756-2651
• DOI: 10.1093/jb/mvx038

Abnormal deposition of the microtubule-associated protein tau is a common pathological feature of multiple neurodegenerative diseases, including Alzheimer's disease (AD), and plays critical roles in their pathogenesis. Disruption of calcium homeostasis and the downstream kinase Ca2+/calmodulin-dependent protein kinase II (CaMKII) coincides with pathological phosphorylation of tau in AD brains. However, it remains unclear whether and how dysregulation of CaMKII affects tau toxicity. Using a Drosophila model, we found that CaMKII promotes neurodegeneration caused by tau phosphorylated at the AD-associated sites Ser262/356. Overexpression of CaMKII promoted, while RNA-mediated knockdown of CaMKII and inhibition of CaMKII activity by expression of an inhibitory peptide suppressed, tau-mediated neurodegeneration. Blocking tau phosphorylation at Ser262/356 by alanine substitutions suppressed promotion of tau toxicity by CaMKII, suggesting that tau phosphorylation at these sites is required for this phenomenon. However, neither knockdown nor overexpression of CaMKII affected tau phosphorylation levels at Ser262/356, suggesting that CaMKII is not directly involved in tau phosphorylation at Ser262/356 in this model. These results suggest that a pathological cascade of events, including elevated levels of tau phosphorylated at Ser262/356 and aberrant activation of CaMKII, work in concert to promote tau-mediated neurodegeneration.