title: Loss of the Batten disease gene CLN3 prevents exit from the TGN of the mannose 6-phosphate receptor.
abstract: The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are a group of inherited childhood-onset neurodegenerative disorders characterized by the lysosomal accumulation of undigested material within cells. To understand this dysfunction, we analysed trafficking of the cation-independent mannose 6-phosphate receptor (CI-MPR), which delivers the digestive enzymes to lysosomes. A common form of NCL is caused by mutations in CLN3, a multipass transmembrane protein of unknown function. We report that ablation of CLN3 causes accumulation of CI-MPR in the trans Golgi network, reflecting a 50% reduction in exit. This CI-MPR trafficking defect is accompanied by a fall in maturation and cellular activity of lysosomal cathepsins. CLN3 is therefore essential for trafficking along the route needed for delivery of lysosomal enzymes, and its loss thereby contributes to and may explain the lysosomal dysfunction underlying Batten disease.
authors.affiliation: MRC Cell Biology Unit, MRC Laboratory for Molecular Cell Biology and Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E6BT, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Metcalf
authors.forename: Alessandra A
authors.initials: AA
authors.lastname: Calvi
authors.forename: Matthew Nj
authors.initials: MNj
authors.lastname: Seaman
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Mitchison
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Cutler
mesh_terms: D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport; D017527:Receptor, IGF Type 2
chemical_list: C105199:CLN3 protein, human; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D017527:Receptor, IGF Type 2