Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy
Open accessAbstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and idiopathic Parkinson's disease. However, the mechanisms for activating its physiological function are not known, hindering identification of the biological role of endogenous LRRK2. The recent discovery that LRRK2 is highly expressed in cells of the innate immune system and genetic association is a risk factor for autoimmune disorders implies an important role for LRRK2 in pathology outside of the central nervous system. Thus, an examination of endogenous LRRK2 in immune cells could provide insight into the protein's function. Here, we establish that stimulation of specific Toll-like receptors results in a complex biochemical activation of endogenous LRRK2, with early phosphorylation of LRRK2 preceding its dimerization and membrane translocation. Membrane-associated LRRK2 co-localized to autophagosome membranes following either TLR4 stimulation or mTOR inhibition with rapamycin. Silencing of endogenous LRRK2 expression resulted in deficits in the induction of autophagy and clearance of a well-described macroautophagy substrate, demonstrating the critical role of endogenous LRRK2 in regulating autophagy. Inhibition of LRRK2 kinase activity also reduced autophagic degradation and suggested the importance of the kinase domain in the regulation of autophagy. Our results demonstrate a well-orchestrated series of biochemical events involved in the activation of LRRK2 important to its physiological function. With similarities observed across multiple cell types and stimuli, these findings are likely relevant in all cell types that natively express endogenous LRRK2, and provide insights into LRRK2 function and its role in human disease.
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TLR2 or TLR4 stimulation can increase the expression and phosphorylation of LRRK2 in microglia.
“Research on microglia has shown that TLR2 or TLR4 stimulation can increase the expression and phosphorylation of LRRK2.259,260”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [260]
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Chu, C. T. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.07.015 · Cited by 218 · see citing works
The Role of LRRK2 in Neurodegeneration of Parkinson Disease
Rui, Q., Ni, H., Li, D., Gao, R., & Chen, G. (2018) · Current Neuropharmacology · doi:10.2174/1570159x16666180222165418 · Cited by 196 · see citing works
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The complex relationships between microglia, alpha-synuclein, and LRRK2 in Parkinson's disease
Schapansky, J., Nardozzi, J. D., & LaVoie, M. J. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2014.09.049 · Cited by 132 · see citing works
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Targeting the Autophagy/Lysosomal Degradation Pathway in Parkinsons Disease
Rivero-Ríos, P., Madero-Pérez, Fernández, B., & Hilfiker, S. (2016) · Current Neuropharmacology · doi:10.2174/1570159x13666151030103027 · Cited by 69 · see citing works
Decoding Parkinson’s Disease Pathogenesis: The Role of Deregulated mRNA Translation
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- Authors
- Schapansky, J., Nardozzi, J. D., Felizia, F., & LaVoie, M. J.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- LaVoie, M. J.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-03-27
- Volume
- 23
- Issue
- 16
- Pages
- 4201-4214
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC4103671
- OpenAlex
- W2123609677
- Cited by
- 226
- References
- 80
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 11 · 2023: 22 · 2022: 23 · 2021: 20 · 2020: 22 · 2019: 22 · 2018: 26 · 2017: 23 · 2016: 16 · 2015: 14 · 2014: 9 · 2012: 1
- FWCI
- 15.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Michael J. Fox Foundation for Parkinson's Research
- National Institutes of Health (AG000222)
- National Institute on Aging (AG000222, T32AG000222)
- National Institute of Neurological Disorders and Stroke (NS072604, R21NS072604)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- LRRK2, autophagy, Parkinson's disease, TLR4, membrane translocation, LRRK2 phosphorylation, mTOR inhibition, rapamycin, LRRK2 kinase activity, innate immune cells, autoimmune disease
- MeSH terms
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Animals, Autophagy, Cell Line, Cell Membrane, Immunosuppressive Agents, Macrophages, Monocytes, Phagocytosis, Phosphorylation, Protein Serine-Threonine Kinases, Microglia, Sirolimus, Protein Transport, Toll-Like Receptor 4, Mice, Protein Multimerization, Gene Knockout Techniques, TOR Serine-Threonine Kinases
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