The long-term goal ofthis research is to understand the molecular mechanisms underlying the phenotypes seen in Down syndrome (DS). DS is a complicated disorder caused by full or partial triplication of chromosome 2 l , and the genotype-phenotype correlations are riot well understood. DS patients have a number of clinical manifestations, including mental retardation, congenital heart defects;motor deficits, and early oriset Alzheimer's disease (AD). DS neuronarcultures and tissues exhibit oxidative damages such as impaired mitochondrial enzyme activities arid increased prbductibn of toxic reactive oxygen species (ROS), Using Drosophila as a model system, we have:previously demonstrated that nebula, the Droisophila homolog of human DSCR1. can regulate protein kinase A and calcineurin activities to alter learning and memory. In addition, we found that nebula is located ih the mitochondria, interacts with the adenine nucleotide ti-ansjocator (ANT), and is important for the maintenance of nriitochondrial functipn and integrity. Mitochondrial dysfunction has recently emerged as a common theme that underlies numerous neurological disorders, including DS and AD. Accordingly, ttie experiments described;in this propiosal are aimed at understanding the effects of perturbed nebula/DSCRI level on mitochohdriarfunction and cell sun/ival, factors controlling its subcellular localization and function, and its possible contribution to AD neuropathologies.
The specific aims are: (1) To determine the physiological consequences of abnormal mitochondrial function due to nebula mutations. (2) To idehttfy signaling pathways regiilatihg nebula localization and fund (3) To investigate whether nebula/DSCRI overexpression contributesi to AD nieuropathologies;
Mitochondrial dysfunction underlies numerous neurologicardisorders,ilnicluding Down syndrome and Alzheimer's disease: Nebula, a protein overexpressed in both DS and ADvaffects mitochondrial funqtiori. In this proposal, we will investigate the roles of nebula in regulating mitochondrial functions in order to better understand Down syndrome and Alzheimeir's disease pathologies
| Shaw, Jillian L; Chang, Karen T (2013) Nebula/DSCR1 upregulation delays neurodegeneration and protects against APP-induced axonal transport defects by restoring calcineurin and GSK-3? signaling. PLoS Genet 9:e1003792 |
| Wang, Wei; Zhu, John Z; Chang, Karen T et al. (2012) DSCR1 interacts with FMRP and is required for spine morphogenesis and local protein synthesis. EMBO J 31:3655-66 |
| Chang, Karen T; Niescier, Robert F; Min, Kyung-Tai (2011) Mitochondrial matrix Ca2+ as an intrinsic signal regulating mitochondrial motility in axons. Proc Natl Acad Sci U S A 108:15456-61 |
| Chang, Karen T; Min, Kyung-Tai (2009) Upregulation of three Drosophila homologs of human chromosome 21 genes alters synaptic function: implications for Down syndrome. Proc Natl Acad Sci U S A 106:17117-22 |
