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Cited by 47Parkinson's Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatments

Extracellular Alpha-Synuclein: Mechanisms for Glial Cell Internalization and Activation

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Chavarría, Cecilia, Ivagnes, Rodrigo, Souza, José M.·2022·Biomolecules
DOI 10.3390/biom12050655PMC PMC9138387
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Abstract

Alpha-synuclein (α-syn) is a small protein composed of 140 amino acids and belongs to the group of intrinsically disordered proteins. It is a soluble protein that is highly expressed in neurons and expressed at low levels in glial cells. The monomeric protein aggregation process induces the formation of oligomeric intermediates and proceeds towards fibrillar species. These α-syn conformational species have been detected in the extracellular space and mediate consequences on surrounding neurons and glial cells. In particular, higher-ordered α-syn aggregates are involved in microglial and oligodendrocyte activation, as well as in the induction of astrogliosis. These phenomena lead to mitochondrial dysfunction, reactive oxygen and nitrogen species formation, and the induction of an inflammatory response, associated with neuronal cell death. Several receptors participate in cell activation and/or in the uptake of α-syn, which can vary depending on the α-syn aggregated state and cell types. The receptors involved in this process are of outstanding relevance because they may constitute potential therapeutic targets for the treatment of PD and related synucleinopathies. This review article focuses on the mechanism associated with extracellular α-syn uptake in glial cells and the consequent glial cell activation that contributes to the neuronal death associated with synucleinopathies.

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  • Extracellular α-synuclein can activate microglia or astrocytes through binding to specific surface receptors (e.g., TLRs, FcγR) or intracellular receptors (e.g., NLRP3).

    “This extracellular α-synuclein can further activate microglia or astrocytes through binding to the specific surface receptors (e.g., TLRs, FcγR) or to intracellular receptors (e.g., NLRP3).49,63,64”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [64]

    Section 2.2 reports α-syn-induced microglial activation through TLR2, and Section 3 says extracellular α-syn can activate proinflammatory TLR4 pathways in astrocytes. Section 3 also reports that α-syn fibrils bind microglial FcγRIIB, but describes inhibited phagocytosis rather than activation through that receptor. The passages found do not support activation through intracellular NLRP3 (searched: NLRP3, inflammasome). No page numbers were provided in our copy. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Chavarría, C., Ivagnes, R., & Souza, J. M.
Affiliations
Universidad de la República de Uruguay (UY)
Corresponding author
Souza, José M.
ORCID
Venue
Biomolecules
Publisher
MDPI AG
Published
2022-04-30
Volume
12
Issue
5
Pages
655
ISSN
2218-273X (ISSN-L)
DOI
10.3390/biom12050655
PMC
PMC9138387
OpenAlex
W4225120349
Cited by
47
References
19
Citations by year
2026: 8 · 2025: 11 · 2024: 14 · 2023: 14
FWCI
1.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomolecules (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Agencia Nacional de Investigación e Innovación (ANII) Uruguay (FCE_1_2019_156706, IDB - R.O.U. (4950/OC-UR), Proyecto de Iniciación)
  • Programa de Alimentos y Salud Humana (PAyS) (FCE_1_2019_156706, IDB - R.O.U. (4950/OC-UR), Proyecto de Iniciación)
  • Comisión Sectorial de Investigación Científica-Universidad de la República del Uruguay (FCE_1_2019_156706, IDB - R.O.U. (4950/OC-UR), Proyecto de Iniciación)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
alpha-synuclein, extracellular alpha-synuclein, glial activation, microglial activation, astrocyte activation, protein aggregation, oligomeric intermediates, mitochondrial dysfunction, oxidative stress, neuroinflammation, neuronal cell death, synucleinopathies, Parkinson's disease, therapeutic target
MeSH terms
Synucleinopathies, Humans, Neuroglia, Parkinson Disease, alpha-Synuclein, Protein Aggregates

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