Fig. 6. Regulation of Itch in Aβ₄₂-induced CRNA.

Aβ₄₂ stimulates aberrant activation of the JNK pathway, which results in hyperphosphorylation of Itch at T222 and S232 by JNK (Fig. 3). The phosphorylation at these sites promotes its autoubiquitination of Itch at K393 (Fig. 4e and f). These post-translational modifications induce TAp73–Itch interaction (Figs. 3d, e and 4c), which results in TAp73 ubiquitination (Fig. 4d, g) and degradation (Fig. 5c–f) and may affect the transcription of TAp73 target genes. Collectively, these events result in cell cycle re-entry and neuronal apoptosis (CRNA; Figs. 2 and 5).