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Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations

Author

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  • Vinay K. Godena

    (University of Sheffield, Firth Court, Western Bank
    The Bateson Centre, University of Sheffield
    Centre for Membrane Interactions and Dynamics, University of Sheffield)

  • Nicholas Brookes-Hocking

    (Institute of Psychiatry, Psychology and Neuroscience, King’s College London)

  • Annekathrin Moller

    (Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield)

  • Gary Shaw

    (Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield)

  • Matthew Oswald

    (University of Sheffield, Firth Court, Western Bank
    The Bateson Centre, University of Sheffield
    Present address: Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ, UK)

  • Rosa M. Sancho

    (Institute of Psychiatry, Psychology and Neuroscience, King’s College London
    Present address: Alzheimer’s Research UK, Unit 3 Riverside, Granta Park, Cambridge CB21 6AD, UK)

  • Christopher C. J. Miller

    (Institute of Psychiatry, Psychology and Neuroscience, King’s College London)

  • Alexander J. Whitworth

    (University of Sheffield, Firth Court, Western Bank
    The Bateson Centre, University of Sheffield
    Centre for Membrane Interactions and Dynamics, University of Sheffield)

  • Kurt J. De Vos

    (Centre for Membrane Interactions and Dynamics, University of Sheffield
    Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield)

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.

Suggested Citation

  • Vinay K. Godena & Nicholas Brookes-Hocking & Annekathrin Moller & Gary Shaw & Matthew Oswald & Rosa M. Sancho & Christopher C. J. Miller & Alexander J. Whitworth & Kurt J. De Vos, 2014. "Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations," Nature Communications, Nature, vol. 5(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6245
    DOI: 10.1038/ncomms6245
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    Cited by:

    1. Aviel Even & Giovanni Morelli & Silvia Turchetto & Michal Shilian & Romain Le Bail & Sophie Laguesse & Nathalie Krusy & Ariel Brisker & Alexander Brandis & Shani Inbar & Alain Chariot & Frédéric Saudo, 2021. "ATP-citrate lyase promotes axonal transport across species," Nature Communications, Nature, vol. 12(1), pages 1-14, December.

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