The plasma alpha-synuclein levels in patients with Parkinson’s disease and multiple system atrophy

Lee, P. H.; Lee, G.; Park, H. J.; Bang, Oh Young; Joo, In Soo; Huh, Kyu Ha

doi:10.1007/s00702-005-0427-9

Cited by 215 publications

(184 citation statements)

References 21 publications

(18 reference statements)

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“…By contrast, α-synuclein is a cytosolic protein, enriched at cytosol/membrane interfaces (49). However, α-synuclein has been identified in extracellular fluids in patients with PD and normal subjects (50)(51)(52)(53). Further, extracellular secretion of α-synuclein is increased under conditions of cellular stress (54); and α-synuclein can also be released in a calcium-dependent manner via exosomes (55).…”

Section: What Is the Mechanism Of Prosaas Protection Against α-Synucleinmentioning

confidence: 99%

The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity

Jarvela

Lam

Helwig

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Emerging evidence strongly suggests that chaperone proteins are cytoprotective in neurodegenerative proteinopathies involving protein aggregation; for example, in the accumulation of aggregated α-synuclein into the Lewy bodies present in Parkinson’s disease. Of the various chaperones known to be associated with neurodegenerative disease, the small secretory chaperone known as proSAAS (named after four residues in the amino terminal region) has many attractive properties. We show here that proSAAS, widely expressed in neurons throughout the brain, is associated with aggregated synuclein deposits in the substantia nigra of patients with Parkinson’s disease. Recombinant proSAAS potently inhibits the fibrillation of α-synuclein in an in vitro assay; residues 158–180, containing a largely conserved element, are critical to this bioactivity. ProSAAS also exhibits a neuroprotective function; proSAAS-encoding lentivirus blocks α-synuclein-induced cytotoxicity in primary cultures of nigral dopaminergic neurons, and recombinant proSAAS blocks α-synuclein–induced cytotoxicity in SH-SY5Y cells. Four independent proteomics studies have previously identified proSAAS as a potential cerebrospinal fluid biomarker in various neurodegenerative diseases. Coupled with prior work showing that proSAAS blocks β-amyloid aggregation into fibrils, this study supports the idea that neuronal proSAAS plays an important role in proteostatic processes. ProSAAS thus represents a possible therapeutic target in neurodegenerative disease.

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Section: What Is the Mechanism Of Prosaas Protection Against α-Synucleinmentioning

confidence: 99%

The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity

Jarvela

Lam

Helwig

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…However, recent studies have suggested that ␣-synuclein also has extracellular pathogenic effects (22)(23)(24)(25). ␣-Synuclein was detected in blood plasma and cerebrospinal fluid in both monomeric and oligomeric forms (22)(23)(24)(25), and the presence of significantly elevated levels of oligomeric species of ␣-synuclein has been reported extracellularly in plasma and cerebrospinal fluid samples from patients with PD (23). Furthermore, various studies have shown that aggregated ␣-synuclein added extracellularly to the culture medium is cytotoxic (26 -32).…”

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

Detecting Morphologically Distinct Oligomeric Forms of α-Synuclein

Emadi

Kasturirangan

Wang

et al. 2009

Journal of Biological Chemistry

124

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Neuropathologic and genetics studies as well as transgenic animal models have provided strong evidence linking misfolding and aggregation of ␣-synuclein to the progression of Parkinson disease (PD) and other related disorders. A growing body of evidence implicates various oligomeric forms of ␣-synuclein as the toxic species responsible for neurodegeneration and neuronal cell death. Although numerous different oligomeric forms of ␣-synuclein have been identified in vitro, it is not known which forms are involved in PD or how, when, and where different forms contribute to the progression of PD. Reagents that can interact with specific aggregate forms of ␣-synuclein would be very useful not only as tools to study how different aggregate forms affect cell function, but also as potential diagnostic and therapeutic agents for PD. Here we show that a single chain antibody fragment (syn-10H scFv) isolated from a phage display antibody library binds to a larger, later stage oligomeric form of ␣-synuclein than a previously reported oligomeric specific scFv isolated in our laboratory. The scFv described here inhibits aggregation of ␣-synuclein in vitro, blocks extracellular ␣-synuclein-induced toxicity in both undifferentiated and differentiated human neuroblastoma cell lines (SH-SY5Y), and specifically recognizes naturally occurring aggregates in PD but not in healthy human brain tissue.

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“…The exocytosis of a-Syn is thought to be linked to a preferential secretion of damaged proteins from the cell (12,14). In this way, it could make its way to both the blood and CSF of both normal and Parkinson's disease-affected individuals (15)(16)(17). The fate of extracellular a-Syn appears to depend on its form, such that a-Syn monomers are degraded by extracellular proteases, such as MMP3 (13), whereas fibrils and oligomers of a-Syn are cleared by endocytosis and lysosomal degradation (18).…”

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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The plasma alpha-synuclein levels in patients with Parkinson’s disease and multiple system atrophy

Cited by 215 publications

References 21 publications

The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity

The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity

Detecting Morphologically Distinct Oligomeric Forms of α-Synuclein

Oligomeric alpha‐synuclein and its role in neuronal death

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