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From Synaptic Protein to Prion: The Long and Controversial Journey of ?-Synuclein.

ABSTRACT: Since its discovery 30 years ago, ?-synuclein (?-syn) has been one of the most studied proteins in the field of neuroscience. Dozens of groups worldwide have tried to reveal not only its role in the CNS but also in other organs. ?-syn has been linked to several processes essential in brain homeostasis such as neurotransmitter release, synaptic function, and plasticity. However, despite the efforts made in this direction, the main function of ?-syn is still unknown. Moreover, ?-syn became a protein of interest for neurologists and neuroscientists when mutations in its gene were found associated with Parkinson's disease (PD) and even more when ?-syn protein deposits were observed in the brain of PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) patients. At present, the abnormal accumulation of ?-syn constitutes one of the pathological hallmarks of these disorders, also referred to as ?-synucleinopathies, and it is used for post-mortem diagnostic criteria. Whether ?-syn aggregation is cause or consequence of the pathogenic events underlying ?-synucleinopathies remains unclear and under discussion. Recently, different in vitro and in vivo studies have shown the ability of pathogenic ?-syn to spread between cells, not only within the CNS but also from peripheral locations such as the gut, salivary glands, and through the olfactory network into the CNS, inducing abnormal misfolding of endogenous ?-syn and leading to neurodegeneration and motor and cognitive impairment in animal models. Thus, it has been suggested that ?-syn should be considered a prion protein. Here we present an update of what we know about ?-syn function, aggregation and spreading, and its role in neurodegeneration. We also discuss the rationale and findings supporting the hypothetical prion nature of ?-syn, its weaknesses, and future perspectives for research and the development of disease-modifying therapies.

SUBMITTER: Heras-Garvin A

PROVIDER: S-EPMC7536368 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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From Synaptic Protein to Prion: The Long and Controversial Journey of α-Synuclein.

Heras-Garvin Antonio A Stefanova Nadia N

Frontiers in synaptic neuroscience 20200921

Since its discovery 30 years ago, α-synuclein (α-syn) has been one of the most studied proteins in the field of neuroscience. Dozens of groups worldwide have tried to reveal not only its role in the CNS but also in other organs. α-syn has been linked to several processes essential in brain homeostasis such as neurotransmitter release, synaptic function, and plasticity. However, despite the efforts made in this direction, the main function of α-syn is still unknown. Moreover, α-syn became a prote ...[more]

PMID: 33071772

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Project description:BACKGROUND:Abnormal aggregation of proteins induces neuronal cell loss in neurodegenerative disorders such as Alzheimer's Disease, Creutzfeldt-Jakob Disease and Parkinson's Disease. Specific stimuli initialize conformational changes in physiological proteins, causing intra- or extracellular protein aggregation. We and other groups have identified naturally occurring autoantibodies (nAbs) as part of the human antibody pool that are able to prevent peptide fibrillation. These nAbs show a rescue effect following exposure of toxic aggregates on neurons, and they support microglial uptake of aggregated peptides. OBJECTIVE:Identification of a putative common epitope among the relevant proteins ?-Amyloid, ?-Synuclein and Prion Protein for the respective nAbs. MATERIAL AND METHODS:Binding affinity between the aforementioned proteins and nAbs was tested by Dot Blot, ELISA and SPR-technology. Furthermore, the functionality of the protein-nAbs-complexes was studied in Thioflavin-T assays and microglial uptake experiments to study dependent inhibition of protein aggregation and enhancement of Fc? mediated uptake by microglial cells. RESULTS:?-Amyloid and Prion Protein fragment showed considerable binding affinity and functional efficacy for all applied nAbs. Thereby, no significant difference within the different nAbs was detected. In contrast, ?-Synuclein was bound exclusively by nAbs-?-Synuclein, which was reproduced in all binding studies. Surprisingly, functional assays with ?-Synuclein revealed no significant effect of nAbs in comparison to IVIg treatment. However, all applied nAbs as well as IVIg show a minimal functionality on the microglial uptake of ?-Synuclein. CONCLUSION:nAbs-A?, nAbs-PrP possibly display comparable affinity to the same structural epitope within A? and PrP106-126 A117V whereas the epitope recognized by nAbs-?-Syn is only present in ?-Syn. The structural similarity of A? and PrP fragment promotes the outline for an efficient antibody for the treatment of several neurodegenerative disorders and extend the functional characteristics of the investigated nAbs.

Dataset Information

From Synaptic Protein to Prion: The Long and Controversial Journey of ?-Synuclein.

Publications

From Synaptic Protein to Prion: The Long and Controversial Journey of α-Synuclein.

Similar Datasets

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