title: Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by TPC2 inhibition.
abstract: Two-pore channels (TPCs) are endolysosomal ion channels implicated in Ca(2+) signalling from acidic organelles. The relevance of these ubiquitous proteins for human disease, however, is unclear. Here, we report that lysosomes are enlarged and aggregated in fibroblasts from Parkinson disease patients with the common G2019S mutation in LRRK2. Defects were corrected by molecular silencing of TPC2, pharmacological inhibition of TPC regulators [Rab7, NAADP and PtdIns(3,5)P2] and buffering local Ca(2+) increases. NAADP-evoked Ca(2+) signals were exaggerated in diseased cells. TPC2 is thus a potential drug target within a pathogenic LRRK2 cascade that disrupts Ca(2+)-dependent trafficking in Parkinson disease.
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: Leanne N
authors.initials: LN
authors.lastname: Hockey
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: Bethan S
authors.initials: BS
authors.lastname: Kilpatrick
authors.affiliation: Department of Cell Biology, Institute of Ophthalmology, University College London, London, EC1V 9EL, UK.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Eden
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, 55455, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Lin-Moshier
authors.affiliation: Department of Pharmaceutical Sciences, Thomas Jefferson University, Jefferson School of Pharmacy, Philadelphia, 19107, USA.
authors.forename: G Cristina
authors.initials: GC
authors.lastname: Brailoiu
authors.affiliation: Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, 19140, USA.
authors.forename: Eugen
authors.initials: E
authors.lastname: Brailoiu
authors.affiliation: Department of Cell Biology, Institute of Ophthalmology, University College London, London, EC1V 9EL, UK.
authors.forename: Clare E
authors.initials: CE
authors.lastname: Futter
authors.affiliation: Department of Clinical Neurosciences, Institute of Neurology, University College London, London, NW3 2PF, UK.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Schapira
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, 55455, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Marchant
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK patel.s@ucl.ac.uk.
authors.forename: Sandip
authors.initials: S
authors.lastname: Patel
mesh_terms: D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D009249:NADP / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; C530224:TPCN2 protein, human; D009249:NADP; C024376:NAADP; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D002118:Calcium
keywords: Ca2+; LRRK2; Lysosomes; NAADP; Parkinson disease; TPCN2