title: The critical role of membralin in postnatal motor neuron survival and disease.
abstract: Hitherto, membralin has been a protein of unknown function. Here, we show that membralin mutant mice manifest a severe and early-onset motor neuron disease in an autosomal recessive manner, dying by postnatal day 5-6. Selective death of lower motor neurons, including those innervating the limbs, intercostal muscles, and diaphragm, is predominantly responsible for this fatal phenotype. Neural expression of a membralin transgene completely rescues membralin mutant mice. Mechanistically, we show that membralin interacts with Erlin2, an endoplasmic reticulum (ER) membrane protein that is located in lipid rafts and known to be important in ER-associated protein degradation (ERAD). Accordingly, the degradation rate of ERAD substrates is attenuated in cells lacking membralin. Membralin mutations or deficiency in mouse models induces ER stress, rendering neurons more vulnerable to cell death. Our study reveals a critical role of membralin in motor neuron survival and suggests a novel mechanism for early-onset motor neuron disease.
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Qu
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States.
authors.forename: Rengang
authors.initials: R
authors.lastname: Wang
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States.
authors.forename: Jon E
authors.initials: JE
authors.lastname: Chatterton
authors.affiliation: Electron Microscopy Laboratory, Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, Davis, United States.
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Liu
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States.
authors.forename: Sonoko
authors.initials: S
authors.lastname: Narisawa
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Millan
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States.
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nakanishi
authors.affiliation: Department of Neurology, Massachusetts General Hospital, , Boston, United States.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Swoboda
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States.
authors.forename: Dongxian
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D002470:Cell Survival / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D060746:Endoplasmic Reticulum-Associated Degradation / Q000502:physiology; D005808:Genes, Recessive; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D006652:Histological Techniques; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D016472:Motor Neuron Disease / Q000235:genetics* / Q000503:physiopathology; D009046:Motor Neurons / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: D017931:DNA Primers; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C475037:Tmem259 protein, mouse; C569219:erlin-2 protein, mouse
keywords: ER membrane protein; ER stress; motor neuron disease; mouse; neuroscience