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G2019S leucine-rich repeat kinase 2 causes uncoupling protein-mediated mitochondrial depolarization
Open accessAbstract
The G2019S leucine rich repeat kinase 2 (LRRK2) mutation is the most common genetic cause of Parkinson's disease (PD), clinically and pathologically indistinguishable from idiopathic PD. Mitochondrial abnormalities are a common feature in PD pathogenesis and we have investigated the impact of G2019S mutant LRRK2 expression on mitochondrial bioenergetics. LRRK2 protein expression was detected in fibroblasts and lymphoblasts at levels higher than those observed in the mouse brain. The presence of G2019S LRRK2 mutation did not influence LRRK2 expression in fibroblasts. However, the expression of the G2019S LRRK2 mutation in both fibroblast and neuroblastoma cells was associated with mitochondrial uncoupling. This was characterized by decreased mitochondrial membrane potential and increased oxygen utilization under basal and oligomycin-inhibited conditions. This resulted in a decrease in cellular ATP levels consistent with compromised cellular function. This uncoupling of mitochondrial oxidative phosphorylation was associated with a cell-specific increase in uncoupling protein (UCP) 2 and 4 expression. Restoration of mitochondrial membrane potential by the UCP inhibitor genipin confirmed the role of UCPs in this mechanism. The G2019S LRRK2-induced mitochondrial uncoupling and UCP4 mRNA up-regulation were LRRK2 kinase-dependent, whereas endogenous LRRK2 levels were required for constitutive UCP expression. We propose that normal mitochondrial function was deregulated by the expression of G2019S LRRK2 in a kinase-dependent mechanism that is a modification of the normal LRRK2 function, and this leads to the vulnerability of selected neuronal populations in PD.
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Cites
PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin
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Self-citationPARIS (ZNF746) Repression of PGC-1α Contributes to Neurodegeneration in Parkinson's Disease
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Kinase activity of mutant LRRK2 mediates neuronal toxicity
Smith, W. W., Pei, Z., Jiang, H., Dawson, V. L., Dawson, T. M., & Ross, C. A. (2006) · Nature Neuroscience · doi:10.1038/nn1776 · Cited by 619
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JNK promotes Bax translocation to mitochondria through phosphorylation of 14‐3‐3 proteins
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Mitochondrial dysfunction in Parkinson's disease
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Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases
Steger, M., Tonelli, F., Ito, G., Davies, P., Trost, M., Vetter, M., Wachter, S., Lorentzen, E., Duddy, G., Wilson, S., et al. (2016) · eLife · doi:10.7554/elife.12813 · Cited by 1,042
Mitochondrial dysfunction and mitophagy in Parkinson's: from familial to sporadic disease
Ryan, B. J., Hoek, S., Fon, E. A., & Wade-Martins, R. (2015) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2015.02.003 · Cited by 524
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Sex differences in Parkinson’s disease
Gillies, G. E., Pienaar, I. S., Vohra, S., & Qamhawi, Z. (2014) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2014.02.002 · Cited by 489
Biological detection by optical oxygen sensing
Papkovsky, D. B., & Dmitriev, R. I. (2013) · Chemical Society Reviews · doi:10.1039/c3cs60131e · Cited by 444
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Metadata
- Authors
- Papkovskaia, T. D., Chau, K.-Y., Inesta-Vaquera, F., Papkovsky, D. B., Healy, D. G., Nishio, K., Staddon, J., Duchen, M. R., Hardy, J., Schapira, A. H. V., & Cooper, J. M.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-06-23
- Volume
- 21
- Issue
- 19
- Pages
- 4201-4213
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2097963493
- Cited by
- 163
- References
- 10
- FWCI
- 8.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Papkovskaia, T. D., Chau, K.-Y., Inesta-Vaquera, F., Papkovsky, D. B., Healy, D. G., Nishio, K., Staddon, J., Duchen, M. R., Hardy, J., Schapira, A. H. V., & Cooper, J. M. (2012). G2019S leucine-rich repeat kinase 2 causes uncoupling protein-mediated mitochondrial depolarization. Human Molecular Genetics. https://doi.org/10.1093/hmg/dds244
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