Alpha-synuclein in the Cerebrospinal Fluid Differentiates Synucleinopathies (Parkinson Disease, Dementia With Lewy Bodies, Multiple System Atrophy) From Alzheimer Disease

Tateno, Fuyuki; Sakakibara, Ryuji; Kawai, Takayuki; Kusumoto, Masahiko; Murano, Takeyoshi

doi:10.1097/wad.0b013e31823899cc

Cited by 115 publications

(90 citation statements)

References 27 publications

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“…pAS was detected in PD samples, which was not the case for oligoAS or oligo-pAS [772]. Confirming several studies showing relatively low CSF AS concentrations in both PD and DLB [731,[773][774][775], more recent ones reported significantly lower AS levels in PD [776,777] as well as in PD, DLB and MSA than in AD [777][778][779]. While CSF levels of AS oligomers were significantly increased in PD patients against controls [298,416,780], AD and progressive supranuclear palsy (PSP) [781], others were unanble to detect oligomeric AS in CSF [776].…”

Section: α-Synuclein As a Biomarker For Synucleinopathiessupporting

confidence: 58%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson's disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

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Section: α-Synuclein As a Biomarker For Synucleinopathiessupporting

confidence: 58%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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“…Interestingly, asynuclein, contrary to Tau and Ab42, is specifically regulated in sCJD. Although increased levels of a-synuclein have been reported in AD cases when compared to controls, these increases range from low to moderate and present no relevant clinical significance [34,38].…”

Section: Discussionmentioning

confidence: 98%

Quantification of CSF biomarkers using an electrochemiluminescence-based detection system in the differential diagnosis of AD and sCJD

et al. 2015

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The identification of reliable diagnostic tools for the differential diagnosis between sporadic Creutzfeldt-Jakob Disease (sCJD) and Alzheimer's disease (AD) remains impeded by the existing clinical, neuropathological and molecular overlap between both diseases. The development of new tools for the quantitative measurement of biomarkers is gaining experimental momentum due to recent advances in high-throughput screening analysis and with the optimization of assays for their quantification in biological fluids, including cerebrospinal fluid (CSF). Electrochemiluminescence (ECL)-based immunoassays have demonstrated to achieve clinical quality performance in a variety of sample types due to its high sensitivity and dynamic range. Here, we quantified the CSF levels of Tau-protein, β-amyloid 1-42 (Aβ42) and α-synuclein, as important biomarkers in CSF used in the differential diagnosis of neurodegenerative disorders in 12 AD, 12 sCJD and 12 control cases by singleplex ECL-based technology. Its performance has been compared to classical enzyme-linked immunosorbent assays (ELISA) to confront their clinical accuracy. ECL-based technology validates previous data obtained with ELISA and presents a higher performance in the discrimination of three analysed groups as determined by increased area under the curve (AUC) values for the three biomarkers. Importantly, α-synuclein levels detected by ECL allow an excellent discrimination between sCJD cases and AD and control cases, unveiling a new clinical approach for the differential diagnosis of sCJD.

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“…CSF a-synuclein in PD and other synucleinopathies is typically reduced [192,193]. In AD and CJD, the levels are elevated and correlate to T-tau, suggesting that a-synuclein may also be an unspecific marker of neurodegeneration [193][194][195][196]. In addition, a-synuclein is highly expressed in red blood cells.…”

Section: Other Protein Inclusionsmentioning

confidence: 95%