The DOI matches its Crossref record; 23 of the 23 references it cites were found in a registry or an index.
Parkin Binds to α/β Tubulin and Increases their Ubiquitination and Degradation
Open accessAbstract
In addition to inhibiting the mitochondrial respiratory chain, toxins known to cause Parkinson9s disease (PD), such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and rotenone, also strongly depolymerize microtubules and increase tubulin degradation. Microtubules are polymers of tubulin α/β heterodimers, whose correct folding requires coordinated actions of cellular chaperonins and cofactors. Misfolded tubulin monomers are highly toxic and quickly degraded through a hitherto unknown mechanism. Here we report that parkin, a protein–ubiquitin E3 ligase linked to PD, was tightly bound to microtubules in taxol-mediated microtubule coassembly assays. In lysates from the rat brain or transfected human embryonic kidney (HEK) 293 cells, α-tubulin and β-tubulin were strongly coimmunoprecipitated with parkin at 4°C in the presence of colchicine, a condition in which tubulin exits as α/β heterodimers. At the subcellular level, parkin exhibited punctate immunostaining along microtubules in rat brain sections, cultured primary neurons, glial cells, and cell lines. This pattern of subcellular localization was abolished in cells treated with the microtubule-depolymerizing drug colchicine. The binding between parkin and tubulin apparently led to increased ubiquitination and accelerated degradation of α- and β-tubulins in HEK293 cells. Similarly ubiquitinated tubulins were also observed in rat brain lysates. Furthermore, parkin mutants found in PD patients did not ubiquitinate or degrade either tubulin. Taken together, our results show that parkin is a novel tubulin-binding protein, as well as a microtubule-associated protein. Its ability to enhance the ubiquitination and degradation of misfolded tubulins may play a significant role in protecting neurons from toxins that cause PD.
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Cites
Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
Kitada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura, Y., Minoshima, S., Yokochi, M., Mizuno, Y., & Shimizu, N. (1998) · Nature · doi:10.1038/33416 · Cited by 5,227
Chronic Parkinsonism in Humans Due to a Product of Meperidine-Analog Synthesis
Langston, J. W., Ballard, P., Tetrud, J. W., & Irwin, I. (1983) · Science · doi:10.1126/science.6823561 · Cited by 4,914
Chronic systemic pesticide exposure reproduces features of Parkinson's disease
Betarbet, R., Sherer, T. B., MacKenzie, G., Garcia-Osuna, M., Panov, A. V., & Greenamyre, J. T. (2000) · Nature Neuroscience · doi:10.1038/81834 · Cited by 3,683
Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase
Shimura, H., Hattori, N., Kubo, S.-I., Mizuno, Y., Asakawa, S., Minoshima, S., Shimizu, N., Iwai, K., Chiba, T., Tanaka, K., et al. (2000) · Nature Genetics · doi:10.1038/77060 · Cited by 2,024 · cited 1×
“…(Cleveland, 1989), the cellular mechanism for the degradation of tubulin in response to these neurotoxins may play a role in PD. Parkin, a gene linked to autosomal recessive juvenile PD (AR- JP) (Kitada et al., 1998) has been found to be a protein– ubiquitin E3 ligase (Shimura et al., 2000).”
BackgroundShimura, H., Schlossmacher, M. G., Hattori, N., Frosch, M. P., Trockenbacher, A., Schneider, R., Mizuno, Y., Kosik, K. S., & Selkoe, D. J. (2001) · Science · doi:10.1126/science.1060627 · Cited by 1,053
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Chung, K. K. K., Zhang, Y., Lim, K. L., Tanaka, Y., Huang, H., Gao, J., Ross, C. A., Dawson, V. L., & Dawson, T. M. (2001) · Nature Medicine · doi:10.1038/nm1001-1144 · Cited by 750
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Lactacystin, Proteasome Function, and Cell Fate
Fenteany, G., & Schreiber, S. L. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.15.8545 · Cited by 410
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
Parkin-deficient Mice Exhibit Nigrostriatal Deficits but Not Loss of Dopaminergic Neurons
Goldberg, M. S., Fleming, S. M., Palacino, J. J., Cepeda, C., Lam, H. A., Bhatnagar, A., Meloni, E. G., Wu, N., Ackerson, L. C., Klapstein, G. J., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m308947200 · Cited by 913
Toxin-induced models of Parkinson’s disease
Bové, J., Prou, D., Perier, C., & Przedborski, S. (2005) · NeuroRX · doi:10.1602/neurorx.2.3.484 · Cited by 739
The tubulin code: Molecular components, readout mechanisms, and functions
Janke, C. (2014) · Journal of Cell Biology · doi:10.1083/jcb.201406055 · Cited by 532
Lim, K. L., Chew, K. C. M., Tan, J. M. M., Wang, C., Chung, K. K. K., Zhang, Y., Tanaka, Y., Smith, W., Engelender, S., Ross, C. A., et al. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.4474-04.2005 · Cited by 503
Metadata
- Authors
- Ren, Y., Zhao, J., & Feng, J.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-04-15
- Volume
- 23
- Issue
- 8
- Pages
- 3316-3324
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- OpenAlex
- W4297062289
- Cited by
- 265
- References
- 23
- FWCI
- 12.43
- Type
- journal article
- Language
- en
- Open access
- bronze
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