RCAN1 in Mitochondrial Dysfunction and Down Syndrome

Ardizzone, Carolyn Anne

Graduate Thesis Or Dissertation

RCAN1 in Mitochondrial Dysfunction and Down Syndrome Public Deposited

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Citeable URL: https://scholar.colorado.edu/concern/graduate_thesis_or_dissertations/kd17ct24x

Abstract

The near-universal early age appearance of Alzheimer’s disease (AD)-related neuropathology in Down syndrome (DS) individuals suggests that factors related to the overexpression of genes on chromosome 21 may be related to the manifestation of AD in the population at large. The product of the gene Regulator of calcineurin 1 (RCAN1), found on chromosome 21 is increased in the brains of DS individuals and is also found elevated in sporadic (non-DS) AD patients. Therefore, the goal of this proposal is to test the hypothesis that RCAN1 overexpression promotes the development of AD-related neuropathology in DS. First, we examined activity of RCAN1’s main substrate, calcineurin (CaN), in DS model (Dp16(1)Yey/+ [Dp16]) neurons in culture using a novel FRET reporter for CaN activity. We found evidence for elevated CaN activity in DS neurons. Second, using DS cell culture models we explored the notion that RCAN1 is important in the manifestation of AD-related phenotypes. Specifically, we explored RCAN1-mediated mitochondrial dysfunction as a potential mechanism through which RCAN1 overexpression leads to the development of AD-related pathology. We found that overexpression of Rcan1 in DS mouse model cell culture promoted abnormal mitochondrial fission leading to reduced mitochondrial size and elevated ROS. Third, we addressed the important question of whether Rcan1 knockdown in DS cell lines eliminates DSlinked AD neuropathology and mitochondrial dysfunction. We found that restoration of RCAN1 levels in Dp16 neuronal culture rescued mitochondrial abnormalities found in Dp16 (Rcan1 trisomic) cells. Finally, using Rcan1 KO cell lines we also examined the idea that particular RCAN1 isoforms were specifically involved in mitochondrial dysfunction. Completion of this project will validate the generation of new tools, including brain specific Rcan1 expression mouse models, and may be of great value to the both the DS and AD research communities.

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