title: A central role for TOR signalling in a yeast model for juvenile CLN3 disease.
abstract: Yeasts provide an excellent genetically tractable eukaryotic system for investigating the function of genes in their biological context, and are especially relevant for those conserved genes that cause disease. We study the role ofbtn1, the orthologue of a human gene that underlies an early onset neurodegenerative disease (juvenile CLN3 disease, neuronal ceroid lipofuscinosis (NCLs) or Batten disease) in the fission yeastSchizosaccharomyces pombe. A global screen for genetic interactions withbtn1highlighted a conserved key signalling hub in which multiple components functionally relate to this conserved disease gene. This signalling hub includes two major mitogen-activated protein kinase (MAPK) cascades, and centers on the Tor kinase complexes TORC1 and TORC2. We confirmed that yeast cells modelling CLN3 disease exhibit features consistent with dysfunction in the TORC pathways, and showed that modulating TORC function leads to a comprehensive rescue of defects in this yeast disease model. The same pathways may be novel targets in the development of therapies for the NCLs and related diseases.
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Bond
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Brown
authors.affiliation: Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK. ; Institute of Healthy Ageing, University College London, London WC1E 6BT, UK.
authors.forename: Charalampos
authors.initials: C
authors.lastname: Rallis
authors.affiliation: Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK. ; Institute of Healthy Ageing, University College London, London WC1E 6BT, UK.
authors.forename: Jürg
authors.initials: J
authors.lastname: Bähler
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK. ; UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. ; Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Mole
keywords: Batten disease; CLN3; NCL; S. pombe; TORC; Tor; btn1; yeast