title: mTOR independent regulation of macroautophagy by Leucine Rich Repeat Kinase 2 via Beclin-1.
abstract: Leucine rich repeat kinase 2 is a complex enzyme with both kinase and GTPase activities, closely linked to the pathogenesis of several human disorders including Parkinson's disease, Crohn's disease, leprosy and cancer. LRRK2 has been implicated in numerous cellular processes; however its physiological function remains unclear. Recent reports suggest that LRRK2 can act to regulate the cellular catabolic process of macroautophagy, although the precise mechanism whereby this occurs has not been identified. To investigate the signalling events through which LRRK2 acts to influence macroautophagy, the mammalian target of rapamycin (mTOR)/Unc-51-like kinase 1 (ULK1) and Beclin-1/phosphatidylinositol 3-kinase (PI3K) pathways were evaluated in astrocytic cell models in the presence and absence of LRRK2 kinase inhibitors. Chemical inhibition of LRRK2 kinase activity resulted in the stimulation of macroautophagy in a non-canonical fashion, independent of mTOR and ULK1, but dependent upon the activation of Beclin 1-containing class III PI3-kinase.
authors.affiliation: School of Pharmacy, University of Reading, Whiteknights, Reading, RG6 6AP, United Kingdom.|Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Claudia
authors.initials: C
authors.lastname: Manzoni
authors.affiliation: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, NIA, NIH, Building 35, 35 Convent Drive, Bethesda, MD 20892-3707, USA.
authors.forename: Adamantios
authors.initials: A
authors.lastname: Mamais
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom.|Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, NIA, NIH, Building 35, 35 Convent Drive, Bethesda, MD 20892-3707, USA.
authors.forename: Dorien A
authors.initials: DA
authors.lastname: Roosen
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Sybille
authors.initials: S
authors.lastname: Dihanich
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Marc P M
authors.initials: MP
authors.lastname: Soutar
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Helene
authors.initials: H
authors.lastname: Plun-Favreau
authors.affiliation: Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, 1 Wakefield Street London WC1N 1PJ, United Kingdom.
authors.forename: Rina
authors.initials: R
authors.lastname: Bandopadhyay
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Francis Crick Institute, London Research Institute, 44 Lincoln's Inn Fields London, WC2A 3LY, United Kingdom.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Tooze
authors.affiliation: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, NIA, NIH, Building 35, 35 Convent Drive, Bethesda, MD 20892-3707, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
authors.affiliation: School of Pharmacy, University of Reading, Whiteknights, Reading, RG6 6AP, United Kingdom.|Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Lewis
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000071189:Autophagy-Related Protein-1 Homolog / Q000378:metabolism; D000071186:Beclin-1 / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000071186:Beclin-1; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D047428:Protein Kinase Inhibitors; D000071189:Autophagy-Related Protein-1 Homolog; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D058570:TOR Serine-Threonine Kinases