A mouse forward genetics screen identifies LISTERIN as an E3 ubiquitin ligase involved in neurodegeneration

摘要: A mouse neurological mutant, lister, was identified through a genome-wide N-ethyl-N-nitrosourea (ENU) mutagenesis screen. Homozygous lister mice exhibit profound early-onset and progressive motor dysfunction. encodes RING finger protein, LISTERIN, which functions as an E3 ubiquitin ligase in vitro. Although is widely expressed all tissues, sensory neurons neuronal processes the brainstem spinal cord are primarily affected mutant. Pathological signs include gliosis, dystrophic neurites, vacuolated mitochondria, accumulation of soluble hyperphosphorylated tau. Analysis with different allele generated targeted gene trap insertion reveals LISTERIN required for embryonic development confirms that direct perturbation LISTERIN-regulated process causes neurodegeneration. The uncovers pathway involved neurodegeneration may serves model understanding molecular mechanisms underlying human neurodegenerative disorders.