ArticleMolecular neurobiology2021
Parkinson's Disease-Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance.
Article in Molecular neurobiology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers, 1 of them a synthesis that pooled it.
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Who cites it
64 citing papers in PubMed, 1 synthesis or guideline pooled it, 122 citations in OpenAlex.
- Molecular Pathways Involved in LRRK2-Linked Parkinson's Disease: A Systematic Review.International journal of molecular sciences · 2022Pooled it
- Leucine-rich repeat kinase 2 (LRRK2): balancing cellular homeostasis and Parkinson's disease (PD) pathogenesis.Annals of medicine · 2026Review
- Current potential biomarkers for Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis: review of literature.Dialogues in clinical neuroscience · 2026Review
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- Convergent Astrocytic Failure in Parkinson's Disease: A System-Level Model of Pathogenesis and Treatment.Molecular neurobiology · 2026Review
- Protocol to quantify LRRK2-mediated Rab10 phosphorylation using high-content imaging.STAR protocols · 2026Article
- Written in the Stars: Astrocyte Biology From Evolution to Disease.Acta physiologica (Oxford, England) · 2026Review
- Dual-Pathway Astrocyte Failure in Parkinson's Disease: Therapeutic Targeting of Nrf2/TFEB Suppression and cGAS-STING/Ferroptosis Activation.Molecular neurobiology · 2026Review
- Astrocytes orchestrate neuroprotection and pathogenesis via bidirectional neuronal interactions in Parkinson's disease.Journal of physiology and biochemistry · 2026Review
- Reactive astrocytes mediate toxicity in iPSC derived dopaminergic neurons.NPJ Parkinson's disease · 2026Article
- Astrocytic dysfunction in Parkinson's disease pathogenesis: focusing on alpha-synuclein.Inflammopharmacology · 2026Review
- A microbiome quantitative trait locus in SLC39A8 modulates disease severity in synucleinopathy-induced models of Parkinson's disease.Human molecular genetics · 2026Article
- Review
- TEM-based Study of the Phenotype of Astrocytes Differentiated from Induced Pluripotent Stem Cells from a Healthy Donor and a Patient with Parkinson's Disease.Sovremennye tekhnologii v meditsine · 2026Article
- Multipath interaction network of annexin A2: multifaceted regulation and translational perspectives in neurological diseases.Frontiers in genetics · 2026Review
- Astrocytes in Parkinson's Disease: From Guardians to Accomplices.Clinical interventions in aging · 2026Review
- Development ofPharmaceuticals (Basel, Switzerland) · 2025Article
- The mCells · 2025Review
- The Effect of Metformin on Astrocytes in Parkinson's Disease: Challenges and Opportunities.Molecular neurobiology · 2025Review
- Glial phagocytosis for synapse and toxic proteins in neurodegenerative diseases.Molecular neurodegeneration · 2025Review
4 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Parkinson's disease (PD) is a neurodegenerative, progressive disease without a cure. To prevent PD onset or at least limit neurodegeneration, a better understanding of the underlying cellular and molecular disease mechanisms is crucial. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent one of the most common causes of familial PD. In addition, LRRK2 variants are risk factors for sporadic PD, making LRRK2 an attractive therapeutic target. Mutations in LRRK2 have been linked to impaired alpha-synuclein (α-syn) degradation in neurons. However, in which way pathogenic LRRK2 affects α-syn clearance by astrocytes, the major glial cell type of the brain, remains unclear. The impact of astrocytes on PD progression has received more attention and recent data indicate that astrocytes play a key role in α-syn-mediated pathology. In the present study, we aimed to compare the capacity of wild-type astrocytes and astrocytes carrying the PD-linked G2019S mutation in Lrrk2 to ingest and degrade fibrillary α-syn. For this purpose, we used two different astrocyte culture systems that were exposed to sonicated α-syn for 24 h and analyzed directly after the α-syn pulse or 6 days later. To elucidate the impact of LRRK2 on α-syn clearance, we performed various analyses, including complementary imaging, transmission electron microscopy, and proteomic approaches. Our results show that astrocytes carrying the G2019S mutation in Lrrk2 exhibit a decreased capacity to internalize and degrade fibrillar α-syn via the endo-lysosomal pathway. In addition, we demonstrate that the reduction of α-syn internalization in the Lrrk2 G2019S astrocytes is linked to annexin A2 (AnxA2) loss of function. Together, our findings reveal that astrocytic LRRK2 contributes to the clearance of extracellular α-syn aggregates through an AnxA2-dependent mechanism.
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