The role of the Ubiquitin Proteolytic Pathway in Axon Degeneration

• Applicants: Professor Michael Coleman, Ph.D.; Dr. Markus Plomann
• Subject Area: Cell Biology
• Term: from 2001 to 2005
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5320132

Wallerian degeneration is an early event in peripheral neuropathy, motor neuron disease and multiple sclerosis. It is the major pathway of axon death, which differs from that of the cell body but is less well studied and poorly understood. We have identified a candidate gene in a mutant mouse, C57BL/Wlds, where Wallerian degeneration is slowed by up to tenfold. It is expressed in neurons and encodes a chimeric protein consisting of the N-terminus of ubiquitin fusion degradation protein 2 (Ufd2) and a C-terminal region of unknown function. These data, together with observations in neurodegenerative mutants, indicate that it is important to study the relationship between the ubiquitin proteolytic pathway and axon degeneration. They also reveal that the Wlds mouse is a useful mutant for investigation of the function of Ufd2. We aim to investigate the downstream consequences of the mutation in Wlds mice by searching for binding partners of the chimeric protein and of each parent protein. We will look for differences in binding partners between Wlds and control mice, such as level of expression, intracellular location and, if appropriate, ubiquitination of any known substrates. We will also investigate the effect of proteasome inhibitors on axon stability. In addition to yielding information about the UPP or other pathways these studies may identify additional proteins important in axon degeneration.

• DFG Programme: Research Grants