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Biomolecules
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Synuclein Proteins
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Synuclein Proteins

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 17741

Special Issue Editors

Dr. Declan McKernan

E-Mail Website
Guest Editor
Pharmacology & Therapeutics, National University of Ireland, H91 W5P7 Galway, Ireland
Interests: neuroinflammation; pattern recognition receptors; schizophrenia
Special Issues, Collections and Topics in MDPI journals
Dr. Xiaobo Mao

E-Mail Website
Guest Editor
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Interests: Parkinson's disease; Alzheimer's disease; alpha-synuclein; tau; LAG3; prion-like protein
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Synucleins are a family of small, soluble proteins expressed in vertebrates whose members include α-synuclein, β-synuclein, and γ-synuclein. All synucleins have a conserved α-helical lipid-binding motif similar to those of apolipoproteins. The α- and β-synuclein proteins are found primarily in brain tissue, where they are seen mainly in presynaptic terminals. The γ-synuclein protein is found primarily in the peripheral nervous system and retina, but also in breast tumours. Cellular functions of the synuclein proteins vary, with data suggesting a common role in the regulation of membrane stability. They have also been demonstrated to form aggregates. Recently, roles in tumour progression and neurodegeneration have been described. Mutations in α-synuclein are associated with rare familial cases of early-onset Parkinson’s disease, and the protein accumulates abnormally forming part of Lewy bodies in Parkinson's disease and several other neurodegenerative illnesses. This Special Issue seeks to understand the normal cellular function of these proteins and how they might contribute to the development of human disease. Original manuscripts and reviews dealing with any aspect of synucleins and related pathophysiology are very welcome.

Dr. Declan P. McKernan
Dr. Xiaobo Mao
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • synuclein native structures & functions
  • synuclein genetics
  • tissue expression and regulation of synucleins
  • synuclein aggregates
  • animal models of synucleinopathies
  • synuclein interacting partners
  • synuclein and neurotransmission
  • synuclein and neurodegeneration
  • synuclein and immune responses

Related Special Issue

Published Papers (6 papers)

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Research

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14 pages, 1810 KiB  
Article
Alpha-Synuclein-Specific Naturally Occurring Antibodies Inhibit Aggregation In Vitro and In Vivo
by Anne K. Braczynski, Marc Sevenich, Ian Gering, Tatsiana Kupreichyk, Emil D. Agerschou, Yannick Kronimus, Pardes Habib, Matthias Stoldt, Dieter Willbold, Jörg B. Schulz, Jan-Philipp Bach, Björn H. Falkenburger and Wolfgang Hoyer
Biomolecules 2022, 12(3), 469; https://doi.org/10.3390/biom12030469 - 18 Mar 2022
Cited by 9 | Viewed by 2771
Abstract
Parkinson’s disease (PD) is associated with motor and non-motor symptoms and characterized by aggregates of alpha-synuclein (αSyn). Naturally occurring antibodies (nAbs) are part of the innate immune system, produced without prior contact to their specific antigen, and polyreactive. The abundance of nAbs against [...] Read more.
Parkinson’s disease (PD) is associated with motor and non-motor symptoms and characterized by aggregates of alpha-synuclein (αSyn). Naturally occurring antibodies (nAbs) are part of the innate immune system, produced without prior contact to their specific antigen, and polyreactive. The abundance of nAbs against αSyn is altered in patients with PD. In this work, we biophysically characterized nAbs against αSyn (nAbs-αSyn) and determined their biological effects. nAbs-αSyn were isolated from commercial intravenous immunoglobulins using column affinity purification. Biophysical properties were characterized using a battery of established in vitro assays. Biological effects were characterized in HEK293T cells transiently transfected with fluorescently tagged αSyn. Specific binding of nAbs-αSyn to monomeric αSyn was demonstrated by Dot blot, ELISA, and Surface Plasmon Resonance. nAbs-αSyn did not affect viability of HEK293T cells as reported by Cell Titer Blue and LDH Assays. nAbs-αSyn inhibited fibrillation of αSyn reported by the Thioflavin T aggregation assay. Altered fibril formation was confirmed with atomic force microscopy. In cells transfected with EGFP-tagged αSyn we observed reduced formation of aggresomes, perinuclear accumulations of αSyn aggregates. The results demonstrate that serum of healthy individuals contains nAbs that specifically bind αSyn and inhibit aggregation of αSyn in vitro. The addition of nAbs-αSyn to cultured cells affects intracellular αSyn aggregates. These findings help understanding the role of the innate immune systems for the pathogenesis of PD and suggest that systemic αSyn binding agents could potentially affect neuronal αSyn pathology. Full article
(This article belongs to the Special Issue Synuclein Proteins)
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18 pages, 5621 KiB  
Article
The Small Molecule Alpha-Synuclein Aggregator, FN075, Enhances Alpha-Synuclein Pathology in Subclinical AAV Rat Models
by Rachel Kelly, Andrew G. Cairns, Jörgen Ådén, Fredrik Almqvist, Alexis-Pierre Bemelmans, Emmanuel Brouillet, Tommy Patton, Declan P. McKernan and Eilís Dowd
Biomolecules 2021, 11(11), 1685; https://doi.org/10.3390/biom11111685 - 12 Nov 2021
Cited by 4 | Viewed by 2142
Abstract
Animal models of Parkinson’s disease, in which the human α-synuclein transgene is overexpressed in the nigrostriatal pathway using viral vectors, are widely considered to be the most relevant models of the human condition. However, although highly valid, these models have major limitations related [...] Read more.
Animal models of Parkinson’s disease, in which the human α-synuclein transgene is overexpressed in the nigrostriatal pathway using viral vectors, are widely considered to be the most relevant models of the human condition. However, although highly valid, these models have major limitations related to reliability and variability, with many animals exhibiting pronounced α-synuclein expression failing to demonstrate nigrostriatal neurodegeneration or motor dysfunction. Therefore, the aim of this study was to determine if sequential intra-nigral administration of AAV-α-synuclein followed by the small α-synuclein aggregating molecule, FN075, would enhance or precipitate the associated α-synucleinopathy, nigrostriatal pathology and motor dysfunction in subclinical models. Rats were given unilateral intra-nigral injections of AAV-α-synuclein (either wild-type or A53T mutant) followed four weeks later by a unilateral intra-nigral injection of FN075, after which they underwent behavioral testing for lateralized motor functionality until they were sacrificed for immunohistological assessment at 20 weeks after AAV administration. In line with expectations, both of the AAV vectors induced widespread overexpression of human α-synuclein in the substantia nigra and striatum. Sequential administration of FN075 significantly enhanced the α-synuclein pathology with increased density and accumulation of the pathological form of the protein phosphorylated at serine 129 (pS129-α-synuclein). However, despite this enhanced α-synuclein pathology, FN075 did not precipitate nigrostriatal degeneration or motor dysfunction in these subclinical AAV models. In conclusion, FN075 holds significant promise as an approach to enhancing the α-synuclein pathology in viral overexpression models, but further studies are required to determine if alternative administration regimes for this molecule could improve the reliability and variability in these models. Full article
(This article belongs to the Special Issue Synuclein Proteins)
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16 pages, 3364 KiB  
Article
Synuclein Family Members Prevent Membrane Damage by Counteracting α-Synuclein Aggregation
by Christian Scheibe, Christiaan Karreman, Stefan Schildknecht, Marcel Leist and Karin Hauser
Biomolecules 2021, 11(8), 1067; https://doi.org/10.3390/biom11081067 - 21 Jul 2021
Cited by 2 | Viewed by 2605
Abstract
The 140 amino acid protein α-synuclein (αS) is an intrinsically disordered protein (IDP) with various roles and locations in healthy neurons that plays a key role in Parkinson’s disease (PD). Contact with biomembranes can lead to α-helical conformations, but can also act as [...] Read more.
The 140 amino acid protein α-synuclein (αS) is an intrinsically disordered protein (IDP) with various roles and locations in healthy neurons that plays a key role in Parkinson’s disease (PD). Contact with biomembranes can lead to α-helical conformations, but can also act as s seeding event for aggregation and a predominant β-sheet conformation. In PD patients, αS is found to aggregate in various fibrillary structures, and the shift in aggregation and localization is associated with disease progression. Besides full-length αS, several related polypeptides are present in neurons. The role of many αS-related proteins in the aggregation of αS itself is not fully understood Two of these potential aggregation modifiers are the αS splicing variant αS Δexon3 (Δ3) and the paralog β-synuclein (βS). Here, polarized ATR-FTIR spectroscopy was used to study the membrane interaction of these proteins individually and in various combinations. The method allowed a continuous monitoring of both the lipid structure of biomimetic membranes and the aggregation state of αS and related proteins. The use of polarized light also revealed the orientation of secondary structure elements. While αS led to a destruction of the lipid membrane upon membrane-catalyzed aggregation, βS and Δ3 aggregated significantly less, and they did not harm the membrane. Moreover, the latter proteins reduced the membrane damage triggered by αS. There were no major differences in the membrane interaction for the different synuclein variants. In combination, these observations suggest that the formation of particular protein aggregates is the major driving force for αS-driven membrane damage. The misbalance of αS, βS, and Δ3 might therefore play a crucial role in neurodegenerative disease. Full article
(This article belongs to the Special Issue Synuclein Proteins)
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Review

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18 pages, 1447 KiB  
Review
α-Synuclein Conformational Plasticity: Physiologic States, Pathologic Strains, and Biotechnological Applications
by Amanda Li, Cyrus Rastegar and Xiaobo Mao
Biomolecules 2022, 12(7), 994; https://doi.org/10.3390/biom12070994 - 17 Jul 2022
Cited by 6 | Viewed by 2760
Abstract
α-Synuclein (αS) is remarkable for both its extensive conformational plasticity and pathologic prion-like properties. Physiologically, αS may populate disordered monomeric, helically folded tetrameric, or membrane-bound oligomeric states. Pathologically, αS may assemble into toxic oligomers and subsequently fibrils, the prion-like transmission of which is [...] Read more.
α-Synuclein (αS) is remarkable for both its extensive conformational plasticity and pathologic prion-like properties. Physiologically, αS may populate disordered monomeric, helically folded tetrameric, or membrane-bound oligomeric states. Pathologically, αS may assemble into toxic oligomers and subsequently fibrils, the prion-like transmission of which is implicated in a class of neurodegenerative disorders collectively termed α-synucleinopathies. Notably, αS does not adopt a single “amyloid fold”, but rather exists as structurally distinct amyloid-like conformations referred to as “strains”. The inoculation of animal models with different strains induces distinct pathologies, and emerging evidence suggests that the propagation of disease-specific strains underlies the differential pathologies observed in patients with different α-synucleinopathies. The characterization of αS strains has provided insight into the structural basis for the overlapping, yet distinct, symptoms of Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies. In this review, we first explore the physiological and pathological differences between conformational states of αS. We then discuss recent studies on the influence of micro-environmental factors on αS species formation, propagation, and the resultant pathological characteristics. Lastly, we review how an understanding of αS conformational properties has been translated to emerging strain amplification technologies, which have provided further insight into the role of specific strains in distinct α-synucleinopathies, and show promise for the early diagnosis of disease. Full article
(This article belongs to the Special Issue Synuclein Proteins)
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25 pages, 1769 KiB  
Review
α-Synuclein at the Presynaptic Axon Terminal as a Double-Edged Sword
by Li Yang Tan, Kwan Hou Tang, Lynette Yu You Lim, Jia Xin Ong, Hyokeun Park and Sangyong Jung
Biomolecules 2022, 12(4), 507; https://doi.org/10.3390/biom12040507 - 27 Mar 2022
Cited by 4 | Viewed by 3875
Abstract
α-synuclein (α-syn) is a presynaptic, lipid-binding protein strongly associated with the neuropathology observed in Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and Alzheimer’s Disease (AD). In normal physiology, α-syn plays a pivotal role in facilitating endocytosis and exocytosis. Interestingly, mutations and modifications [...] Read more.
α-synuclein (α-syn) is a presynaptic, lipid-binding protein strongly associated with the neuropathology observed in Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and Alzheimer’s Disease (AD). In normal physiology, α-syn plays a pivotal role in facilitating endocytosis and exocytosis. Interestingly, mutations and modifications of precise α-syn domains interfere with α-syn oligomerization and nucleation that negatively affect presynaptic vesicular dynamics, protein expressions, and mitochondrial profiles. Furthermore, the integration of the α-syn oligomers into the presynaptic membrane results in pore formations, ion influx, and excitotoxicity. Targeted therapies against specific domains of α-syn, including the use of small organic molecules, monoclonal antibodies, and synthetic peptides, are being screened and developed. However, the prospect of an effective α-syn targeted therapy is still plagued by low permeability across the blood–brain barrier (BBB), and poor entry into the presynaptic axon terminals. The present review proposes a modification of current strategies, which includes the use of novel encapsulation technology, such as lipid nanoparticles, to bypass the BBB and deliver such agents into the brain. Full article
(This article belongs to the Special Issue Synuclein Proteins)
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Other

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21 pages, 7742 KiB  
Systematic Review
The Effect of Aggregated Alpha Synuclein on Synaptic and Axonal Proteins in Parkinson’s Disease—A Systematic Review
by Jennifer Murphy and Declan P. McKernan
Biomolecules 2022, 12(9), 1199; https://doi.org/10.3390/biom12091199 - 29 Aug 2022
Cited by 4 | Viewed by 2015
Abstract
α-synuclein is a core component of Lewy bodies, one of the pathological hallmarks of Parkinson’s disease. Aggregated α-synuclein can impair both synaptic functioning and axonal transport. However, understanding the pathological role that α-synuclein plays at a cellular level is complicated as existing findings [...] Read more.
α-synuclein is a core component of Lewy bodies, one of the pathological hallmarks of Parkinson’s disease. Aggregated α-synuclein can impair both synaptic functioning and axonal transport. However, understanding the pathological role that α-synuclein plays at a cellular level is complicated as existing findings are multifaceted and dependent on the mutation, the species, and the quantity of the protein that is involved. This systematic review aims to stratify the research findings to develop a more comprehensive understanding of the role of aggregated α-synuclein on synaptic and axonal proteins in Parkinson’s disease models. A literature search of the PubMed, Scopus, and Web of Science databases was conducted and a total of 39 studies were included for analysis. The review provides evidence for the dysregulation or redistribution of synaptic and axonal proteins due to α-synuclein toxicity. However, due to the high quantity of variables that were used in the research investigations, it was challenging to ascertain exactly what effect α-synuclein has on the expression of the proteins. A more standardized experimental approach regarding the variables that are employed in future studies is crucial so that existing literature can be consolidated. New research involving aggregated α-synuclein at the synapse and regarding axonal transport could be advantageous in guiding new treatment solutions. Full article
(This article belongs to the Special Issue Synuclein Proteins)
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