title: Late-onset of spinal neurodegeneration in knock-in mice expressing a mutant BiP.
abstract: Most human neurodegenerative diseases are sporadic, and appear later in life. While the underlying mechanisms of the progression of those diseases are still unclear, investigations into the familial forms of comparable diseases suggest that endoplasmic reticulum (ER) stress is involved in the pathogenesis. Binding immunoglobulin protein (BiP) is an ER chaperone that is central to ER function. We produced knock-in mice expressing a mutant BiP that lacked the retrieval sequence in order to evaluate the effect of a functional defect in an ER chaperone in multi-cellular organisms. Here we report that heterozygous mutant BiP mice revealed motor disabilities in aging. We found a degeneration of some motoneurons in the spinal cord accompanied by accumulations of ubiquitinated proteins. The defect in retrieval of BiP by the KDEL receptor leads to impaired activities in quality control and autophagy, suggesting that functional defects in the ER chaperones may contribute to the late onset of neurodegenerative diseases.
authors.affiliation: Department of Anesthesiology, Chiba University Graduate School of Medicine, Chiba City, Chiba, Japan.
authors.forename: Hisayo
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Medicine and Clinical Oncology, Chiba University Graduate School of Medicine, Chiba City, Chiba, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Mimura
authors.affiliation: Department of Anesthesiology, Chiba University Graduate School of Medicine, Chiba City, Chiba, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Kashio
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.affiliation: Department of Anesthesiology, Chiba University Graduate School of Medicine, Chiba City, Chiba, Japan; Department of Anesthesiology, Tokyo Women's Medical University, Yachiyo Medical, Center, Yachiyo, Chiba, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Aoe
mesh_terms: D000367:Age Factors; D000818:Animals; D015153:Blotting, Western; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D055879:Gene Knock-In Techniques; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000235:genetics*; D006652:Histological Techniques; D006801:Humans; D000067562:Late Onset Disorders / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D008856:Microscopy, Fluorescence; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000503:physiopathology*; D018000:Receptors, Peptide / Q000378:metabolism; D014415:Tunicamycin
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C064459:KDEL receptor; D018000:Receptors, Peptide; D014415:Tunicamycin