title: Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations.
abstract: Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease. LRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Defective microtubule-based axonal transport is hypothesized to contribute to Parkinson's disease, but whether LRRK2 mutations affect this process to mediate pathogenesis is not known. Here we find that LRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila, causing locomotor deficits in vivo. In vitro, increasing microtubule acetylation using deacetylase inhibitors or the tubulin acetylase αTAT1 prevents association of mutant LRRK2 with microtubules, and the deacetylase inhibitor trichostatin A (TSA) restores axonal transport. In vivo knockdown of the deacetylases HDAC6 and Sirt2, or administration of TSA rescues both axonal transport and locomotor behavior. Thus, this study reveals a pathogenic mechanism and a potential intervention for Parkinson's disease.
authors.affiliation: 1] Department of Biomedical Sciences, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK [2] The Bateson Centre, University of Sheffield, Sheffield S10 2TN, UK [3] Centre for Membrane Interactions and Dynamics, University of Sheffield, Sheffield S10 2TN, UK.
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Godena
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Brookes-Hocking
authors.affiliation: Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield S10 2HQ, UK.
authors.forename: Annekathrin
authors.initials: A
authors.lastname: Moller
authors.affiliation: Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield S10 2HQ, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Shaw
authors.affiliation: 1] Department of Biomedical Sciences, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK [2] The Bateson Centre, University of Sheffield, Sheffield S10 2TN, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Oswald
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Sancho
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
authors.forename: Christopher C J
authors.initials: CC
authors.lastname: Miller
authors.affiliation: 1] Department of Biomedical Sciences, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK [2] The Bateson Centre, University of Sheffield, Sheffield S10 2TN, UK [3] Centre for Membrane Interactions and Dynamics, University of Sheffield, Sheffield S10 2TN, UK.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Whitworth
authors.affiliation: 1] Centre for Membrane Interactions and Dynamics, University of Sheffield, Sheffield S10 2TN, UK [2] Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield S10 2HQ, UK.
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: De Vos
mesh_terms: D000107:Acetylation; D000818:Animals; D001369:Axons / Q000201:enzymology; D001692:Biological Transport; D002465:Cell Movement; D004330:Drosophila; D029721:Drosophila Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008870:Microtubules / Q000378:metabolism*; D009154:Mutation; D009474:Neurons / Q000201:enzymology; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats
chemical_list: D029721:Drosophila Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; C495280:LRRK2 protein, human; C543697:LRRK protein, Drosophila