Evaluation of Dyrk1a as a Therapeutic Target for Rescuing Behavioral and Bone Deficits in the Ts65Dn Mouse Model for Down syndrome

Roshni Patel Indiana University-Purdue University Indianapolis
Faculty Sponsor(s): Randall Roper Indiana University-Purdue University Indianapolis, Charles Goodlett Indiana University-Purdue University Indianapolis
Elucidation of the underlying mechanisms involved in both behavioral and bone-related deficits of Down syndrome (DS) would be useful towards identifying targets for treatment development. Several genes associated with DS-specific phenotypes have been hypothesized as therapeutic targets. One such gene of interest is DYRK1A, which has been implicated in the development and maintenance of both brain-related functions and bone physiology. Increased Dyrk1a dosage results in behavioral deficits in cognition and cerebellar motor functions as well as an osteoporotic-like phenotype characterized by reduced bone mass and strength, which are reminiscent of the phenotypes seen in individuals with DS. To evaluate the efficacy of DYRK1A modulation in ameliorating behavioral deficits, including hippocampal, cerebellar, and broader cortex-related deficits, as well as bone deficits in the context of DS, we have normalized the Dyrk1a copy number in Ts65Dn mice, a DS mouse model, and assessed bone architecture, bone strength, cognition, and motor behaviors. Preliminary results indicate that Dyrk1a normalization improves bone architecture and hippocampal-based performance in a Morris water maze task, but not cerebellar motor-based balance beam performances or novel object recognition in comparison to age-matched euploid mice. Behavioral and bone measures will also been correlated with functional levels of Dyrk1a-related kinase activity in hippocampus, cerebellum, cortex, and bone tissues using an HPLC-based assay. Analyzed together, these results will predict the therapeutic value of normalizing Dyrk1a in improving DS-related phenotypes.
Oral Presentation

When & Where

12:15 PM
Gallahue Hall 101