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

TitleIncreasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations.
Publication TypeJournal Article
Year of Publication2014
AuthorsGodena, VK, Brookes-Hocking, N, Moller, A, Shaw, G, Oswald, M, Sancho, RM, Miller, CCJ, Whitworth, AJ, De Vos, KJ
JournalNat Commun
Volume5
Pagination5245
Date Published2014 Oct 15
ISSN2041-1723
KeywordsAcetylation, Animals, Axons, Biological Transport, Cell Movement, Drosophila, Drosophila Proteins, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Microtubules, Mutation, Neurons, Parkinson Disease, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Rats
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.

DOI10.1038/ncomms6245
Alternate JournalNat Commun
Citation Key10.1038/ncomms6245
PubMed ID25316291
PubMed Central IDPMC4208097
Grant List078662 / / Wellcome Trust / United Kingdom
G-0813 / / Parkinson's UK / United Kingdom
P40 OD018537 / OD / NIH HHS / United States
MC_G1000735 / / Medical Research Council / United Kingdom
089698 / / Wellcome Trust / United Kingdom
G0501573 / / Medical Research Council / United Kingdom
P40OD018537 / OD / NIH HHS / United States
309742 / / European Research Council / International
MR/K005146/1 / / Medical Research Council / United Kingdom
GR077544AIA / / Wellcome Trust / United Kingdom