The DOI matches its Crossref record; 68 of the 68 references it cites were found in a registry or an index.
Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations
Open accessAbstract
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.
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Cites
Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
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Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1
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Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology
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Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease
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HDAC6 is a microtubule-associated deacetylase
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“Both the class IIb member HDAC6 and class III member SIRT2 have been shown to deacetylate α -tubulin 28,29 and conversely their inhibition increases microtubule acetylation.”
Genome-wide association study reveals genetic risk underlying Parkinson's disease
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Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity
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Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants
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Self-citation
Cited by
The tubulin code and its role in controlling microtubule properties and functions
Janke, C., & Magiera, M. M. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0214-3 · Cited by 956
Mitochondrial dysfunction and mitophagy in parkinson’s disease: from mechanism to therapy
Malpartida, A. B., Williamson, M., Narendra, D. P., Wade-Martins, R., & Ryan, B. J. (2021) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2020.11.007 · Cited by 482
HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients
Guo, W., Naujock, M., Fumagalli, L., Vandoorne, T., Baatsen, P., Boon, R., Ordovás, L., Patel, A., Welters, M., Vanwelden, T., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00911-y · Cited by 373
Effects of α-tubulin acetylation on microtubule structure and stability
Eshun-Wilson, L., Zhang, R., Portran, D., Nachury, M. V., Toso, D. B., Löhr, T., Vendruscolo, M., Bonomi, M., Fraser, J. S., & Nogales, E. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1900441116 · Cited by 361
Axonal transport and neurological disease
Sleigh, J. N., Rossor, A. M., Fellows, A. D., Tosolini, A. P., & Schiavo, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0257-2 · Cited by 316
Metadata
- Authors
- Godena, V. K., Brookes-Hocking, N., Moller, A., Shaw, G., Oswald, M., Sancho, R. M., Miller, C. C. J., Whitworth, A. J., & De Vos, K. J.
- Venue
- Nature Communications
- Published
- 2014-10-15
- Volume
- 5
- Issue
- 1
- Pages
- 5245-5245
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2039073478
- Cited by
- 280
- References
- 68
- FWCI
- 13.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Godena, V. K., Brookes-Hocking, N., Moller, A., Shaw, G., Oswald, M., Sancho, R. M., Miller, C. C. J., Whitworth, A. J., & De Vos, K. J. (2014). Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations. Nature Communications. https://doi.org/10.1038/ncomms6245
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