ArticleGlia2021
Extracellular clusterin limits the uptake of α-synuclein fibrils by murine and human astrocytes.
Article in Glia, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 46 citations in OpenAlex.
- Brain region-resolved pharmacodynamics of an antisense oligonucleotide targeting human SNCA 3'UTR in BAC-hSNCA rats.Translational neurodegeneration · 2026Article
- HDAC6 Inhibition Reduces Seeded Tau and α-Synuclein Pathologies in Primary Neuron Cultures and Wild-Type Mice.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Extracellular LCN2 Binding to 24p3R in Astrocytes Impedes α-Synuclein Endocytosis in Parkinson's Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- LRRK2-Mediated Neuroinflammation-Induced Neuronal Dysfunctions in a Parkinson's and Alzheimer's Disease Cellular Model.Biomolecules · 2025Article
- Glial phagocytosis for synapse and toxic proteins in neurodegenerative diseases.Molecular neurodegeneration · 2025Review
- Aerobic exercise-induced changes in fluid biomarkers in Parkinson's disease.NPJ Parkinson's disease · 2025Review
- The Emerging Role of the Molecular Chaperone Clusterin in Parkinson's Disease.International journal of molecular sciences · 2025Review
- Astrocytes carrying LRRK2 G2019S exhibit increased levels of clusterin chaperone via miR-22-5p and reduced ability to take up α-synuclein fibrils.Acta neuropathologica communications · 2025Article
- Astrocytic RNA editing regulates the host immune response to alpha-synuclein.Science advances · 2025Article
- Astrocytic and microglial cell functions in neuroinflammatory diseases and their animal models.Frontiers in cellular neuroscience · 2025Review
- Clusterin: structure, function and roles in disease.International journal of medical sciences · 2025Review
- Brain clearance of protein aggregates: a close-up on astrocytes.Molecular neurodegeneration · 2024Review
- Clusterin: a double-edged sword in cancer and neurological disorders.EXCLI journal · 2024Review
- Pharmacogenomics of Dementia: Personalizing the Treatment of Cognitive and Neuropsychiatric Symptoms.Genes · 2023Review
- Uncovering the Role of Natural and Synthetic Small Molecules in Counteracting the Burden of α-Synuclein Aggregates and Related Toxicity in Different Models of Parkinson's Disease.International journal of molecular sciences · 2023Review
- Article
- Shared genetic risk loci between Alzheimer's disease and related dementias, Parkinson's disease, and amyotrophic lateral sclerosis.Alzheimer's research & therapy · 2023Article
- Potential Role of Protein Kinase FAM20C on the Brain in Raine Syndrome, an In Silico Analysis.International journal of molecular sciences · 2023Article
- Cntnap4 partial deficiency exacerbates α-synuclein pathology through astrocyte-microglia C3-C3aR pathway.Cell death & disease · 2023Article
- The function of previously unappreciated exerkines secreted by muscle in regulation of neurodegenerative diseases.Frontiers in molecular neuroscience · 2023Review
Corrections and comments
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Authors and funding
20 authors at 5 institutions in 2 countries.
Funding
Abstract
The progressive neuropathological damage seen in Parkinson's disease (PD) is thought to be related to the spreading of aggregated forms of α-synuclein. Clearance of extracellular α-synuclein released by degenerating neurons may be therefore a key mechanism to control the concentration of α-synuclein in the extracellular space. Several molecular chaperones control misfolded protein accumulation in the extracellular compartment. Among these, clusterin, a glycoprotein associated with Alzheimer's disease, binds α-synuclein aggregated species and is present in Lewy bodies, intraneuronal aggregates mainly composed by fibrillary α-synuclein. In this study, using murine primary astrocytes with clusterin genetic deletion, human-induced pluripotent stem cell (iPSC)-derived astrocytes with clusterin silencing and two animal models relevant for PD we explore how clusterin affects the clearance of α-synuclein aggregates by astrocytes. Our findings showed that astrocytes take up α-synuclein preformed fibrils (pffs) through dynamin-dependent endocytosis and that clusterin levels are modulated in the culture media of cells upon α-synuclein pffs exposure. Specifically, we found that clusterin interacts with α-synuclein pffs in the extracellular compartment and the clusterin/α-synuclein complex can be internalized by astrocytes. Mechanistically, using clusterin knock-out primary astrocytes and clusterin knock-down hiPSC-derived astrocytes we observed that clusterin limits the uptake of α-synuclein pffs by cells. Interestingly, we detected increased levels of clusterin in the adeno-associated virus- and the α-synuclein pffs- injected mouse model, suggesting a crucial role of this chaperone in the pathogenesis of PD. Overall, our observations indicate that clusterin can limit the uptake of extracellular α-synuclein aggregates by astrocytes and, hence, contribute to the spreading of Parkinson pathology.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.