Deletion of critical mediators of ubiquitination and NAD synheses: the effects on neurodegeneration

• Antragsteller: Professor Michael Coleman, Ph.D.
• Fachliche Zuordnung: Nuklearmedizin, Strahlentherapie, Strahlenbiologie
• Förderung: Förderung von 2002 bis 2005
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 5393685

We have discovered a mutant gene, Wlds, encoding a unique protective factor for axons in injury and disease. The Wlds protein ist a fusion of the N-terminus of multi-ubiquitination factor Ube4b, and the entire coding region of the NAD synthesising enzyme Nmnat. By deleting essential elements of the UBe4b and Nmnat genes, we aim to investigate the normal roles of each Wlds parent gene and study the effects of manipulating (acelerating or delaying) Wallerian degeneration in neurodegenrative discorders. We have already made significant steps towards complete and conditional deletions: for Nmnat we habe a germline transmission of the floxed allele and healthy hemizygous knockout mice, for Ube4b two homologously recomdined ES cell clones. A gene-trap clone of Ube4b is also avialable. We will study the deletion mutants in several models of neurodegeneration. Firstly, we will look for signs of spontaneous axon degeneration in central or peripheral nervous system. Secondly, we will test for an altered rate of Wallerian degeneration induced by sciatic nerve injury. Thirdly, we will cross deletion mutants with Wlds mice. We will also use the mutant mice to investigate the wider roles of each gene in neurodegeneration, which could include PARP-1 mediated necrosis and Parkinsonism.

• DFG-Verfahren: Sachbeihilfen