Author
Listed:
- 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
Download full text from publisher
Corrections
All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6245. See general information about how to correct material in RePEc.
If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.
We have no bibliographic references for this item. You can help adding them by using this form .
If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.
For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .
Please note that corrections may take a couple of weeks to filter through
the various RePEc services.