A Novel E3 Ubiquitin Ligase Involved in Neurodegeneration
Masuda, C.A.1,2; Chu, J.1; Hong, N.3; Wu, H.3; Li, W.2; Bengtson, M.H.2; Joazeiro, C.A.2; Kay, S.A.1
1. The Scripps Research Institute, La Jolla, CA, USA; 2. Genomics Institute of the Novartis Research Foundation, San Diego, CA, USA; 3. Phenomix Corp., San Diego, CA, USA.
Dysfunctions of the ubiquitin-proteasome pathway have been implicated in a number of neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease and polyglutamine disorders.
During a mouse ENU forward genetic screening for neurological mutants, we have identified a recessive mutation that causes several motor dysfunctions including loss of hind limb extension reflex, progressive weakness and atrophy of skeletal muscles in hind limbs, and eventually paralysis and death within 5 months. Histophathological analysis showed loss of motor neurons in the spinal cord, axonal degeneration, ubiquitin-positive aggregates and astroglyosis in the spinal cord and brain stem. Hyperphosphorylated forms of tau protein were also detected in immunoblotting experiments. The mutation was mapped to a gene encoding a RING-finger containing protein. This protein presented E3 ubiquitin ligase activity in vitro and had its expression decreased in affected animals.
We are currently investigating the biological functions of this new E3 ubiquitin ligase in order to understand how a mutation in this gene causes neurodegeneration.
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