The DOI matches its Crossref record; 17 of the 17 references it cites were found in a registry or an index.
Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP
Open accessAbstract
Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause late-onset Parkinson's disease, but its physiological function has remained largely unknown. Here we report that LRRK2 activates a calcium-dependent protein kinase kinase-β (CaMKK-β)/adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway which is followed by a persistent increase in autophagosome formation. Simultaneously, LRKR2 overexpression increases the levels of the autophagy receptor p62 in a protein synthesis-dependent manner, and decreases the number of acidic lysosomes. The LRRK2-mediated effects result in increased sensitivity of cells to stressors associated with abnormal protein degradation. These effects can be mimicked by the lysosomal Ca(2+)-mobilizing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) and can be reverted by an NAADP receptor antagonist or expression of dominant-negative receptor constructs. Collectively, our data indicate a molecular mechanism for LRRK2 deregulation of autophagy and reveal previously unidentified therapeutic targets.
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Cites
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Cited by
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Metadata
- Authors
- Gómez-Suaga, P., Luzón-Toro, B., Churamani, D., Zhang, L., Bloor-Young, D., Patel, S., Woodman, P. G., Churchill, G. C., & Hilfiker, S.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-10-19
- Volume
- 21
- Issue
- 3
- Pages
- 511-525
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2096905204
- Cited by
- 312
- References
- 17
- FWCI
- 19.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Gómez-Suaga, P., Luzón-Toro, B., Churamani, D., Zhang, L., Bloor-Young, D., Patel, S., Woodman, P. G., Churchill, G. C., & Hilfiker, S. (2012). Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. Human Molecular Genetics. https://doi.org/10.1093/hmg/ddr481
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