Dyrk1A-mediated phosphorylation of RCAN1 promotes the formation of insoluble RCAN1 aggregates

• RCAN1 self-associates and forms multimers.
• RCAN1 multimer formation is promoted by the Dyrk1A-mediated phosphorylation.
• Phospho-RCAN1 expression is lower in aged Dyrk1A TG mice than in littermates.
• Dyrk1A plays a role in the formation of insoluble RCAN1 aggregates upon aging.

The mechanisms underlying aggregate formation in age-related neurodegenerative diseases remain not well understood. Here we investigated whether dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (Dyrk1A) is involved in the formation of regulator of calcineurin 1 (RCAN1) aggregates. We show that RCAN1 self-associates and forms multimers, and that this process is promoted by the Dyrk1A-mediated phosphorylation of RCAN1 at the Thr192 residue. Transgenic mice that overexpress the Dyrk1A exhibited lower levels of phospho-Thr192-RCAN1 in 10-month-old-group compared to littermate controls, when analyzed with soluble hippocampus lysates. These results suggest that the phosphorylation of RCAN1 by Dyrk1A stimulates the formation of insoluble aggregates upon aging.