title: Characterisation of early changes in ovine CLN5 and CLN6 Batten disease neural cultures for the rapid screening of therapeutics.
abstract: Batten disease (neuronal ceroid lipofuscinosis) refers to a group of neurodegenerative lysosomal storage diseases predominantly affecting children. There are currently no effective treatments, and the functions of many of the associated gene products are unknown. Here we characterise fetal neural cultures from two genetically distinct sheep forms of Batten disease, with mutations in the lysosomal protein encoding gene CLN5 and endoplasmic reticulum membrane protein encoding gene CLN6, respectively. We found similar reductions in autophagy, acidic organelles and synaptic recycling in both forms compared to unaffected cells. We then developed a high-throughput screen and tested for correction of deficient cells with lentiviral-mediated CLN5 or CLN6 gene transfer and fibrate drugs, gemfibrozil and fenofibrate in CLN6 deficient neural cultures. These assays provide a simple system to rapidly screen candidate therapies or libraries of drugs prior to in vivo testing.
authors.affiliation: Department of Biochemistry, School of Biomedical Sciences, Brain Health Research Centre, University of Otago, Dunedin, New Zealand; Batten Animal Research Network (BARN), New Zealand.
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Best
authors.affiliation: Department of Biochemistry, School of Biomedical Sciences, Brain Health Research Centre, University of Otago, Dunedin, New Zealand; Batten Animal Research Network (BARN), New Zealand.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Neverman
authors.affiliation: Department of Biochemistry, School of Biomedical Sciences, Brain Health Research Centre, University of Otago, Dunedin, New Zealand; Batten Animal Research Network (BARN), New Zealand.
authors.forename: Hollie E
authors.initials: HE
authors.lastname: Wicky
authors.affiliation: Faculty of Agriculture and Life Sciences, Lincoln University, Canterbury, New Zealand; Batten Animal Research Network (BARN), New Zealand.
authors.forename: Nadia L
authors.initials: NL
authors.lastname: Mitchell
authors.affiliation: Department of Anatomy, School of Biomedical Sciences, Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
authors.forename: Beulah
authors.initials: B
authors.lastname: Leitch
authors.affiliation: Department of Biochemistry, School of Biomedical Sciences, Brain Health Research Centre, University of Otago, Dunedin, New Zealand; Batten Animal Research Network (BARN), New Zealand. Electronic address: stephanie.hughes@otago.ac.nz.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Hughes
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D008247:Lysosomes / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000378:metabolism*; D012756:Sheep
chemical_list: D008565:Membrane Proteins
keywords: Autophagy; Batten disease; CLN5; CLN6; Gene therapy; Neuronal cell culture; Neuronal ceroid lipofuscinosis