Neurodegenerative disorders such as Alzheimer's and Parkinson's disease are common and devastating diseases, but the mechanism leading to neuronal death is not well understood. Mice with mutations in the Attractin (Atrn) and Mahogunin (Mgn) genes develop progressive spongy degeneration of the brain and thus represent newly recognized models of neurodegeneration. These mutants also have a coat color phenotype due to a defect in a pigment-cell specific pathway. The similarity between Atrn and Mgn mutants for two unrelated phenotypes suggests a common function for these genes. While the role of Atrn in neurons is unclear, Mgn encodes a RING-finger containing protein that acts as a ubiquitin ligase (E3) in vitro. Accumulation of ubiquitinated protein aggregates is a hallmark of many neurodegenerative disorders and mutations in another E3, Parkin, cause a familial form of Parkinson's disease. Thus, we hypothesize that defects in ubiquitin-mediated degradation of specific target proteins lead to neuronal death in Atrn and Mgn mutants. The long-term goal of research in the Gunn laboratory is to determine how. ? ? The short term goals are to test the following hypotheses: ? 1) that Mgn functions as an E3 in vivo, by testing whether the RING domain of Mgn (required for E3 activity in vitro) is essential for normal Mgn function in vivo, and by identifying Mgn-interacting proteins using a yeast two hybrid assay and using biochemical assays to test whether these proteins are targeted by Mgn for ubiquitin-mediated decay and accumulate in the brains of Mgn mutant mice. ? 2) that Mgn and Atrn act in the same pathway, using marker gene expression, western analysis and/or immunohistochemistry to examine Mgn levels and localization in Atrn mutants and determine whether proteins identified as Mgn targets for ubiquitination accumulate in the brains of Atrn mutant mice. ? 3) that a newly discovered Atrn homolog, Lurin, signals through the Mgn pathway, by generating mice ? lacking Lurin and examining their phenotype (including accumulation of Mgn targets) on normal and Atrn null backgrounds. As Mgn mutants display some phenotypes not observed in Atrn mutants, Lrn may compensate for loss of Atrn in some tissues and loss of both Lrn and Atrn may recapitulate the full Mgn phenotype. ? ?
| Gunn, Teresa M; Silvius, Derek; Bagher, Pooneh et al. (2013) MGRN1-dependent pigment-type switching requires its ubiquitination activity but not its interaction with TSG101 or NEDD4. Pigment Cell Melanoma Res 26:263-8 |
| Jiao, Jian; Kim, Hae Young; Liu, Roy R et al. (2009) Transgenic analysis of the physiological functions of Mahogunin Ring Finger-1 isoforms. Genesis 47:524-34 |
| Jiao, Jian; Sun, Kaihua; Walker, Will P et al. (2009) Abnormal regulation of TSG101 in mice with spongiform neurodegeneration. Biochim Biophys Acta 1792:1027-35 |
| Sun, Kaihua; Johnson, Brian S; Gunn, Teresa M (2007) Mitochondrial dysfunction precedes neurodegeneration in mahogunin (Mgrn1) mutant mice. Neurobiol Aging 28:1840-52 |
| Walker, Will P; Aradhya, Swaroop; Hu, Che-Lin et al. (2007) Genetic analysis of attractin homologs. Genesis 45:744-56 |
| Bagher, Pooneh; Jiao, Jian; Owen Smith, C et al. (2006) Characterization of Mahogunin Ring Finger-1 expression in mice. Pigment Cell Res 19:635-43 |
