The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice
Open accessAbstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. LRRK2 is a large protein containing a small GTPase domain and a kinase domain, but its physiological role is unknown. To identify the normal function of LRRK2 in vivo, we generated two independent lines of germ-line deletion mice. The dopaminergic system of LRRK2 −/− mice appears normal, and numbers of dopaminergic neurons and levels of striatal dopamine are unchanged. However, LRRK2 −/− kidneys, which suffer the greatest loss of LRRK compared with other organs, develop striking accumulation and aggregation of α-synuclein and ubiquitinated proteins at 20 months of age. The autophagy–lysosomal pathway is also impaired in the absence of LRRK2, as indicated by accumulation of lipofuscin granules as well as altered levels of LC3-II and p62. Furthermore, loss of LRRK2 dramatically increases apoptotic cell death, inflammatory responses, and oxidative damage. Collectively, our findings show that LRRK2 plays an essential and unexpected role in the regulation of protein homeostasis during aging, and suggest that LRRK2 mutations may cause Parkinson's disease and cell death via impairment of protein degradation pathways, leading to α-synuclein accumulation and aggregation over time.
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“To assess further autophagy function in the absence of LRRK2, we evaluated markers of autophagosomes, such as microtubuleassociated protein 1 light chain 3 (LC3), a homolog of Atg8, which is essential for autophagy function in yeast (20, 21).”
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Cited by
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Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy
Muzio, L., Viotti, A., & Martino, G. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.742065 · Cited by 581
Defects in trafficking bridge Parkinson’s disease pathology and genetics
Abeliovich, A., & Gitler, A. D. (2016) · Nature · doi:10.1038/nature20414 · Cited by 462
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Metadata
- Authors
- Tong, Y., Yamaguchi, H., Giaime, E., Boyle, S., Kopan, R., Kelleher, R. J., & Shen, J.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2010-05-10
- Volume
- 107
- Issue
- 21
- Pages
- 9879-9884
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2110157421
- Cited by
- 501
- References
- 9
- FWCI
- 27.44
- Type
- journal article
- Language
- en
- Open access
- green
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- Tong, Y., Yamaguchi, H., Giaime, E., Boyle, S., Kopan, R., Kelleher, R. J., & Shen, J. (2010). Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1004676107
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