A mouse forward genetics screen identifies LISTERIN as an E3 ubiquitin ligase involved in neurodegeneration.
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 neurological and motor dysfunction. lister encodes a RING finger protein, LISTERIN, which functions as an E3 ubiquitin ligase in vitro. Although lister is widely expressed in all tissues, motor and sensory neurons and neuronal processes in the brainstem and spinal cord are primarily affected in the mutant. Pathological signs include gliosis, dystrophic neurites, vacuolated mitochondria, and accumulation of soluble hyperphosphorylated tau. Analysis with a different lister allele generated through targeted gene trap insertion reveals LISTERIN is required for embryonic development and confirms that direct perturbation of a LISTERIN-regulated process causes neurodegeneration. The lister mouse uncovers a pathway involved in neurodegeneration and may serves as a model for understanding the molecular mechanisms underlying human neurodegenerative disorders.
Chu
Jessie
J
Department of Biochemistry, Institute for Childhood and Neglected Diseases, The Scripps Research Institute, ICND216, 10550 North Torrey Pines Road, La Jolla, CA 90237, USA.
Hong
Nancy A
NA
Masuda
Claudio A
CA
Jenkins
Brian V
BV
Nelms
Keats A
KA
Goodnow
Christopher C
CC
Glynne
Richard J
RJ
Wu
Hua
H
Masliah
Eliezer
E
Joazeiro
Claudio A P
CA
Kay
Steve A
SA
D000483:Alleles; D000818:Animals; D001369:Axons; D005838:Genotype; D006720:Homozygote; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D016296:Mutagenesis; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics*; D010641:Phenotype; D014018:Tissue Distribution; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
C539338:Ltn1 protein, mouse; D044767:Ubiquitin-Protein Ligases