Parkinson's disease (PD) is the second most common neurodegenerative disorder in the United States. Recently, several families with Autosomal Recessive Juvenile Parkinsonism (AR-JP) have been demonstrated to carry mutations in a gene termed Parkin, a ubiquitin E3 ligase. NINDS recently identified Parkin and related proteins as targets for intensive investigation (RFA NS-01-005). In this proposal, we focus on Ariadne, the closest known structural homolog of Parkin. Ariadne is a poorly characterized protein with a similar overall structural organization to Parkin. Both Ariadne and Parkin bind to the same ubiquitin E2 enzymes and in Drosophila, loss of Ariadne results in reduced viability and resting tremors. In preliminary studies, we have demonstrated that Ariadne and Parkin share significant structural and functional properties.In this proposal, we will use biochemical, molecular, cellular and genetic methods to test thehypotheses that Ariadne and Parkin are: 1) structural and functional homologs; 2) participate in Lewy Body formation; and 3) protect cells both in vitro and in vivo from noxious stimuli.This work may allow us to: 1) explain why the phenotypic effects of global loss-of-function mutations in Parkin are largely restricted to dopaminergic neurons; 2) verify that Lewy Body-like cytoplasmic inclusions reflect an adaptive response by cells; and 3 provide insight into the functioning of this class of proteins which can enhance our understanding of Parkin function in cells.
| Kim, Chul; Srivastava, Sapeckshita; Rice, Marian et al. (2011) Expression of human amyloid precursor protein in the skeletal muscles of Drosophila results in age- and activity-dependent muscle weakness. BMC Physiol 11:7 |
| Wang, Zhaohui; Glenn, Honor; Brown, Christine et al. (2009) Regulation of muscle differentiation and survival by Acheron. Mech Dev 126:700-9 |
| Gao, Zheng-Liang; Deblis, Ryan; Glenn, Honor et al. (2007) Differential roles of HIC-5 isoforms in the regulation of cell death and myotube formation during myogenesis. Exp Cell Res 313:4000-14 |
