AlphaLISA detection of alpha-synuclein in the cerebrospinal fluid and its potential application in Parkinson’s disease diagnosis

Zhao, Hongli; Zhao, Jue; Hou, J.P.; Wang, Siqing; Ding, Yu; Lu, Boxun; Wang, Jian

doi:10.1007/s13238-017-0424-4

Cited by 10 publications

(6 citation statements)

References 11 publications

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“…Apart from potential future therapeutic implications, the ability of the amphipathic cationic helical peptides to bind to αS toxic species with high affinity might find a direct application in diagnosis. The presence of αS aggregates in biofluids is considered a biomarker for PD and other synucleopathies 48 , 49 . However, current detection methods are not specific and sensitive enough for their clinical implementation.…”

Section: Discussionmentioning

confidence: 99%

α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity

et al. 2021

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Abstractα-Synuclein aggregation is a key driver of neurodegeneration in Parkinson’s disease and related syndromes. Accordingly, obtaining a molecule that targets α-synuclein toxic assemblies with high affinity is a long-pursued objective. Here, we exploit the biophysical properties of toxic oligomers and amyloid fibrils to identify a family of α-helical peptides that bind to these α-synuclein species with low nanomolar affinity, without interfering with the monomeric functional protein. This activity is translated into a high anti-aggregation potency and the ability to abrogate oligomer-induced cell damage. Using a structure-guided search we identify a human peptide expressed in the brain and the gastrointestinal tract with analogous binding, anti-aggregation, and detoxifying properties. The chemical entities we describe here may represent a therapeutic avenue for the synucleinopathies and are promising tools to assist diagnosis by discriminating between native and toxic α-synuclein species.

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Section: Discussionmentioning

confidence: 99%

α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity

et al. 2021

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“…However, oligomeric tau molecules in close enough proximity could generate an AlphaLISA signal by providing multiple epitopes for the HA antibody to bind. Other groups have already taken advantage of this system and published assays for similar oligomerizing proteins, such as for alpha-synuclein 54 .…”

Section: Co-expression Of Neuronal Tau and Astrocytic Hapoeε4 Increasmentioning

confidence: 99%

Astrocytic expression of the Alzheimer’s disease risk allele, ApoEε4, potentiates neuronal tau pathology in multiple preclinical models

Jablonski

Warren

Usenovic

et al. 2021

Sci Rep

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ApoEε4 is a major genetic risk factor for Alzheimer’s disease (AD), a disease hallmarked by extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). The presence of the ApoEε4 allele is associated with increased Aβ deposition and a role for ApoEε4 in the potentiation of tau pathology has recently emerged. This study focused on comparing the effects of adeno-associated virus (AAV)-mediated overexpression of the three predominant human ApoE isoforms within astrocytes. The isoform-specific effects of human ApoE were evaluated within in vitro models of tau pathology within neuron/astrocyte co-cultures, as well as in a transgenic tau mouse model. Tau aggregation, accumulation, and phosphorylation were measured to determine if the three isoforms of human ApoE had differential effects on tau. Astrocytic overexpression of the human ApoEε4 allele increased phosphorylation and misfolding of overexpressed neuronal tau in multiple models, including the aggregation and accumulation of added tau oligomers, in an isoform-specific manner. The ability of ApoEε4 to increase tau aggregation could be inhibited by an ApoEε4-specific antibody. This study indicates that astrocytic expression of ApoEε4 can potentiate tau aggregation and phosphorylation within neurons and supports a gain of toxic function hypothesis for the effect of hApoEε4 on tau.

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“…Apart from their therapeutic implications, the ability of the amphipathic cationic helical peptides to bind to αS toxic species with high affinity and selectivity might find a direct application in diagnosis. The presence of αS aggregates in biofluids is considered a biomarker for PD and other synucleopathies 45, 46 . However, current detection methods are not specific and sensitive enough for their clinical implementation.…”

Section: Discussionmentioning

confidence: 99%

α-Helical peptidic scaffolds to target α-synuclein pathogenic species with high affinity and selectivity

Santos

Gracia

Navarro

et al. 2021

Preprint

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α-Synuclein aggregation is a key driver of neurodegeneration in Parkinsons disease and related syndromes. Accordingly, obtaining a molecule that targets α-synuclein pathogenic assemblies with high affinity and selectivity is a long-pursued objective. Here, we have exploited the biophysical properties of toxic oligomers and amyloid fibrils to identify a family of α-helical peptides that bind selectively to these α-synuclein species with low nanomolar affinity, without interfering with the monomeric functional protein. This activity is translated into an unprecedented anti-aggregation potency and the ability to abrogate the oligomers toxicity. With a structure-function relationship in hand, we identified a human peptide expressed in the brain and in the gastrointestinal tract with exceptional binding, anti-aggregation, and detoxifying properties, which suggests it might play a protective role against synucleinopathies. The chemical entities we describe here represent a new therapeutic paradigm and are promising tools to assist diagnosis by selectively detecting α-synuclein pathogenic species in biofluids.

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AlphaLISA detection of alpha-synuclein in the cerebrospinal fluid and its potential application in Parkinson’s disease diagnosis

Cited by 10 publications

References 11 publications

α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity

α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity

Astrocytic expression of the Alzheimer’s disease risk allele, ApoEε4, potentiates neuronal tau pathology in multiple preclinical models

α-Helical peptidic scaffolds to target α-synuclein pathogenic species with high affinity and selectivity

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