α‐Synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma

El‐Agnaf, Omar M. A.; Salem, Sultan A.; Paleologou, Katerina E.; Cooper, Leanne J.; Fullwood, Nigel J.; Gibson, Mark J.; Curran, Martin D.; Court, Jennifer A.; Mann, David; Ikeda, Shu‐ichi; Cookson, Mark; Hardy, John; Allsop, David

doi:10.1096/fj.03-0098fje

Cited by 554 publications

(475 citation statements)

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“…a-Syn can leave cells via various mechanisms including secretion and, more specifically, exocytosis (Figure 2a). Multiple forms of a-syn have been detected in cerebrospinal fluid, blood plasma, [44][45][46] and more recently, in saliva, 47 indicating a secretory process. Monomers and aggregated forms of a-syn are secreted from neuroblastoma cells overexpressing a-syn and from rat primary cortical neurons.…”

Section: Molecular Mechanisms Involved In Intercellular Transfer Of Amentioning

confidence: 99%

A deadly spread: cellular mechanisms of α-synuclein transfer

2011

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Classically, Parkinson's disease (PD) is linked to dopamine neuron death in the substantia nigra pars compacta. Intracytoplasmic protein inclusions named Lewy bodies, and corresponding Lewy neurites found in neuronal processes, are also key features of the degenerative process in the substantia nigra. The molecular mechanisms by which substantia nigra dopamine neurons die and whether the Lewy pathology is directly involved in the cell death pathway are open questions. More recently, it has become apparent that Lewy pathology gradually involves greater parts of the PD brain and is widespread in late stages. In this review, we first discuss the role of misfolded a-synuclein protein, which is the main constituent of Lewy bodies, in the pathogenesis of PD. We then describe recent evidence that a-synuclein might transfer between cells in PD brains. We discuss in detail the possible molecular mechanisms underlying the proposed propagation and the likely consequences for cells that take up a-synuclein. Finally, we focus on aspects of the pathogenic process that could be targeted with new pharmaceutical therapies or used to develop biomarkers for early PD detection. Multiple hypotheses exist to help explain dopamine neuron cell death and Lewy body formation observed in Parkinson's disease (PD). Mutations of the main proteinaceous constituent of Lewy bodies, a-synuclein (a-syn), lead to dominant, familial disease forms. [1][2][3][4][5] More recently, genome-wide association studies (GWASs) identified variants of the a-synuclein gene (SNCA) gene, encoding a-syn protein, that are coupled to increased PD susceptibility, thus clearly linking this protein to idiopathic PD. 6-8 Furthermore, overexpressed and/or misfolded a-syn is pathogenic to cells while a-syn can be secreted from cells, enter other cells, and seed small intracellular aggregates, demonstrating a connection between a-syn and pathogenic mechanisms of PD. [9][10][11][12][13][14][15][16] In parallel, a much-discussed hypothesis by Braak and colleagues 17 states that a pathogenic agent, introduced via ingestion and/or inhalation, may transfer from the entry site along known long, unmyelinated axons to basal brain areas and eventually to brain stem and cortical regions. Although a-syn is unlikely to be this initial pathogen, it might be the initial target of the unknown agent. If a-syn is misfolded because of the action of the unknown agent, it might contribute to the spreading of pathology by moving from one cell to another and triggering misfolding in the recipient cells. If so, it might explain the surprising presence of Lewy bodies in the young neural grafts of transplanted PD patients observed more than a decade after surgery. [18][19][20][21] In this review, we discuss possible mechanisms by which a-syn could spread between cells and have deadly consequences by describing the molecular evidence for a-syn cellular exit, transit to other cells, uptake by cells, intracellular aggregation, and responses to a-syn accumulation.The Relationship Between a-Syn and PD ...

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Section: Molecular Mechanisms Involved In Intercellular Transfer Of Amentioning

confidence: 99%

A deadly spread: cellular mechanisms of α-synuclein transfer

2011

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“…However, the presence of a-Syn in the cerebrospinal fluid (CSF) of Parkinson's disease patients does support the possibility that aggregates of the protein exist outside of cell. aSyn may be released upon cell death (10) or secreted from neuronal cells, as evidenced in culture (11)(12)(13). The exocytosis of a-Syn is thought to be linked to a preferential secretion of damaged proteins from the cell (12,14).…”

Section: Alpha-synuclein and Neurotoxicitymentioning

confidence: 99%

Oligomeric alpha‐synuclein and its role in neuronal death

Brown

2010

IUBMB Life

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SummaryAlpha-synuclein is a natively unfolded protein associated with a number of neurodegenerative disorders that include Parkinson's disease. In the past, research has focused on the fibrillar form of the protein. Current research now indicates that oligomeric alpha-synuclein is the form of the protein most likely to causes neuronal death. Recent research has suggested that a unique oligomer associated with the copper binding capacity of the protein is the neurotoxic form of the protein. This review looks at the evidence for this possibility.

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“…α-synuclein is also detectable in both human CSF and plasma in soluble, oligomeric forms that may have use as potential biomarkers for PD [59,60]. α-synuclein secretion appears to be mediated by an unconventional mechanism, independent of the ER/Golgi [61,62].…”

Section: Escape Of Aggregates From Neuronsmentioning

confidence: 99%

“…Release of α-synuclein may occur through multiple mechanisms, however. Free α-synuclein can be immunoprecipitated from media and human CSF [60], and at least a subset of the toxic species in conditioned media is removed via α-synuclein-specific immunoprecipitation [61]. Calcium-mediated exosome release may also contribute to secretion, as α-synuclein can be found in the exosomal fraction of conditioned media [61,63].…”

Section: Escape Of Aggregates From Neuronsmentioning

confidence: 99%