The complex relationships between microglia, alpha-synuclein, and LRRK2 in Parkinson's disease
Open accessAbstract
The proteins alpha-synuclein (αSyn) and leucine rich repeat kinase 2 (LRRK2) are both key players in the pathogenesis of the neurodegenerative disorder Parkinson's disease (PD), but establishing a functional link between the two proteins has proven elusive. Research studies for these two proteins have traditionally and justifiably focused in neuronal cells, but recent studies indicate that each protein could play a greater pathological role elsewhere. αSyn is expressed at high levels within neurons, but they also secrete the protein into the extracellular milieu, where it can have broad ranging effects in the nervous system and relevance to disease etiology. Similarly, low neuronal LRRK2 expression and activity suggests that LRRK2-related functions could be more relevant in cells with higher expression, such as brain-resident microglia. Microglia are monocytic immune cells that protect neurons from noxious stimuli, including pathological αSyn species, and microglial activation is believed to contribute to neuroinflammation and neuronal death in PD. Interestingly, both αSyn and LRRK2 can be linked to microglial function. Secreted αSyn can directly activate microglia, and can be taken up by microglia for clearance, while LRRK2 has been implicated in the intrinsic regulation of microglial activation and of lysosomal degradation processes. Based on these observations, the present review will focus on how PD-associated mutations in LRRK2 could potentially alter microglial biology with respect to neuronally secreted αSyn, resulting in cell dysfunction and neurodegeneration.
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The LRRK2 gene can promote clearance of α-syn.
“The clearance of α-syn also can be promoted by the leucine-rich repeat kinase 2 (LRRK2) gene.”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Schapansky et al., 2015
Pathogenic mutations in LRRK2 influence the ability of microglia to internalize and degrade α-syn, exacerbating α-syn-induced microglial pathology and neuroinflammation.
“Pathogenic mutations in LRRK2 influence the ability of microglia to internalize and degrade α-syn, exacerbating α-syn-induced microglial pathology, and neuroinflammation (Schapansky et al., 2015).”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Schapansky et al., 2015
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- Authors
- Schapansky, J., Nardozzi, J. D., & LaVoie, M. J.
- Affiliations
- Brigham and Women's Hospital (US)
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 302
- Pages
- 74-88
- ISSN
- 0306-4522 (ISSN-L)
- PMC
- PMC4383729
- OpenAlex
- W1988160418
- Cited by
- 132
- References
- 212
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 9 · 2023: 7 · 2022: 10 · 2021: 11 · 2020: 15 · 2019: 15 · 2018: 18 · 2017: 19 · 2016: 14 · 2015: 9
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Michael J. Fox Foundation
- National Institutes of Health (NS072604)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, microglia, alpha-synuclein, LRRK2, microglial activation, neuroinflammation, extracellular alpha-synuclein, lysosomal degradation, LRRK2 mutations, neurodegeneration
- MeSH terms
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Animals, Humans, Parkinson Disease, Protein Serine-Threonine Kinases, Microglia, alpha-Synuclein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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