title: Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival.
abstract: CLEC16A is in a locus genetically linked to autoimmune diseases including multiple sclerosis, but the function of this gene in the nervous system is unknown. Here we show that two mouse strains carrying independent Clec16a mutations developed neurodegenerative disease characterized by motor impairments and loss of Purkinje cells. Neurons from Clec16a-mutant mice exhibited increased expression of the autophagy substrate p62, accumulation of abnormal intra-axonal membranous structures bearing the autophagy protein LC3, and abnormal Golgi morphology. Multiple aspects of endocytosis, lysosome and Golgi function were normal in Clec16a-deficient murine embryonic fibroblasts and HeLa cells. However, these cells displayed abnormal bulk autophagy despite unimpaired autophagosome formation. Cultured Clec16a-deficient cells exhibited a striking accumulation of LC3 and LAMP-1 positive autolysosomes containing undigested cytoplasmic contents. Therefore Clec16a, an autophagy protein that is critical for autolysosome function and clearance, is required for Purkinje cell survival.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Veronika
authors.initials: V
authors.lastname: Redmann
authors.affiliation: The Francis Crick Institute, Lincoln's Inn Fields Laboratory, London, WC2A 3LY, UK.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lamb
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Seungmin
authors.initials: S
authors.lastname: Hwang
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Orchard
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sungsu
authors.initials: S
authors.lastname: Kim
authors.affiliation: The Francis Crick Institute, Lincoln's Inn Fields Laboratory, London, WC2A 3LY, UK.
authors.forename: Minoo
authors.initials: M
authors.lastname: Razi
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Milam
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sunmin
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Christine C
authors.initials: CC
authors.lastname: Yokoyama
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Amal
authors.initials: A
authors.lastname: Kambal
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Darren
authors.initials: D
authors.lastname: Kreamalmeyer
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Marie K
authors.initials: MK
authors.lastname: Bosch
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Maolei
authors.initials: M
authors.lastname: Xiao
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Green
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Jungsu
authors.initials: J
authors.lastname: Kim
authors.affiliation: Genome Engineering and iPSC Center, Washington University School of Medicine, St. Louis, MO 63110, USA.|Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Shondra M
authors.initials: SM
authors.lastname: Pruett-Miller
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Ornitz
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Allen
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Wandy L
authors.initials: WL
authors.lastname: Beatty
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schmidt
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: DiAntonio
authors.affiliation: The Francis Crick Institute, Lincoln's Inn Fields Laboratory, London, WC2A 3LY, UK.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Tooze
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.|Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.|Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
mesh_terms: D000818:Animals; D001343:Autophagy; D002470:Cell Survival; D002478:Cells, Cultured; D006056:Golgi Apparatus / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics* / Q000378:metabolism; D008247:Lysosomes / Q000502:physiology*; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000235:genetics* / Q000378:metabolism; D016472:Motor Neuron Disease / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D011689:Purkinje Cells / Q000166:cytology*
chemical_list: C522505:CLEC16A protein, human; C000591253:CLEC16A protein, mouse; D037181:Lectins, C-Type; D009004:Monosaccharide Transport Proteins