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The Structure and Function of Synuclein
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The Structure and Function of Synuclein

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (10 February 2024) | Viewed by 7343

Special Issue Editors

Prof. Dr. Kenjiro Ono

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Guest Editor
Department of Neurology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8640, Japan
Interests: neurology; dementia; Alzheimer’s disease; Lewy body diseases; amyloid, oligomer; protein aggregation
Special Issues, Collections and Topics in MDPI journals
Dr. Takafumi Hasegawa

E-Mail Website
Guest Editor
Department of Neurology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
Interests: neurodegeneration; Parkinson's disease; multiple system atrophy; synuclein vesicular trafficking
Dr. Kazuma Murakami

E-Mail Website
Guest Editor
Division of Food Science and Biotechnology, Kyoto University, Kyoto 606-8502, Japan
Interests: neurodegenerative diseases; neurobiology; neurological diseases

Special Issue Information

Dear Colleagues,

Parkinson’s disease (PD) is the most common type of parkinsonism that cause movement problems such as rigidity, slowness, and tremor. More than six million individuals worldwide have PD. The disease is characterized by the death of dopaminergic neurons in the substantia nigra. The pathologic hallmark of PD is the Lewy body (LB), a neuronal inclusion largely consisting of α-synuclein (αS) protein aggregations, which are associated with the death of dopamine-producing cells. In advanced PD, the pathology progresses to the cerebral cortices and is concomitant with the onset of cognitive impairment and hallucinations. Currently, the supplementation of dopamine is the mainstay of PD treatment, since no means to modify its pathogenesis have yet been identified.

Dementia with Lewy bodies (DLB) is a slowly progressive and persistent dementia disorder of the elderly, clinically characterized by fluctuating attention, recurrent visual hallucinations, and parkinsonism. As with PD, LBs and Lewy neurites in the brain constitute the main histopathological features of DLB.

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by progressive autonomic failure, parkinsonism, and cerebellar and pyramidal tract symptoms. Glial cytoplasmic inclusions of αS are a defining histologic feature of this disease.

Taken together with biochemical and genetic evidence, the mis-folding and aggregation of αS may play an important role in the development of α-synucleinopathies, including PD, DLB, and MSA.

αS tends to fold and aggregate to form oligomers, protofibrils, and mature fibrils, potentially causing neuronal dysfunction in the pathogenesis of α-synucleinopathies.

This Special Issue focusses on the current understanding and future research directions regarding the structure and function of synuclein in neurodegenerative diseases. We warmly welcome original manuscripts, review articles, case reports, and commentaries relating to this hot topic.

Prof. Dr. Kenjiro Ono
Dr. Takafumi Hasegawa
Dr. Kazuma Murakami
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • Lewy body
  • glial cytoplasmic inclusions
  • α-synuclein
  • aggregation
  • structure
  • oligomer
  • Parkinson’s disease
  • dementia with Lewy bodies
  • multiple system atrophy
  • α-synucleinopathies
  • neurodegeneration
  • predictive markers
  • disease-modifying therapy

Published Papers (4 papers)

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Research

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18 pages, 14631 KiB  
Article
The 75–99 C-Terminal Peptide of URG7 Protein Promotes α-Synuclein Disaggregation
by Jany Dandurand, Magnus Monné, Valérie Samouillan, Martina Rosa, Alessandro Laurita, Alessandro Pistone, Donatella Bisaccia, Ilenia Matera, Faustino Bisaccia and Angela Ostuni
Int. J. Mol. Sci. 2024, 25(2), 1135; https://doi.org/10.3390/ijms25021135 - 17 Jan 2024
Cited by 2 | Viewed by 769
Abstract
Up Regulation Gene seven (URG7) is the pseudogene 2 of the transporter ABCC6. The translated URG7 protein is localized with its single transmembrane α-helix in the endoplasmic reticulum (ER) membrane, orienting the N- and C-terminal regions in the lumen and cytoplasm, respectively, and [...] Read more.
Up Regulation Gene seven (URG7) is the pseudogene 2 of the transporter ABCC6. The translated URG7 protein is localized with its single transmembrane α-helix in the endoplasmic reticulum (ER) membrane, orienting the N- and C-terminal regions in the lumen and cytoplasm, respectively, and it plays a crucial role in the folding of ER proteins. Previously, the C-terminal region of URG7 (PU, residues 75–99) has been shown to modify the aggregation state of α-synuclein in the lysate of HepG2 cells. PU analogs were synthesized, and their anti-aggregation potential was tested in vitro on α-synuclein obtained using recombinant DNA technology. Circular dichroism (CD), differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) spectroscopy, and microscopic techniques were used to assess the sample’s behavior. The results show that the peptides studied by themselves are prone to clathrate-like structure formation of variable stability. Aggregation of α-synuclein is accompanied by desolvation of its peptide chain and an increase in intermolecular β-sheets. The PU analogs all interact with α-synuclein aggregates and those possessing the most stable clathrate-like structures have the highest disaggregating effect. These findings suggest that the C-terminal region of URG7 may have a role in interacting and modulating α-synuclein structures and could be used to generate interesting therapeutic candidates as disaggregators of α-synuclein. Full article
(This article belongs to the Special Issue The Structure and Function of Synuclein)
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Review

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38 pages, 1460 KiB  
Review
Alpha-Synuclein Contribution to Neuronal and Glial Damage in Parkinson’s Disease
by Kamil Saramowicz, Natalia Siwecka, Grzegorz Galita, Aleksandra Kucharska-Lusina, Wioletta Rozpędek-Kamińska and Ireneusz Majsterek
Int. J. Mol. Sci. 2024, 25(1), 360; https://doi.org/10.3390/ijms25010360 - 26 Dec 2023
Cited by 3 | Viewed by 2129
Abstract
Parkinson’s disease (PD) is a complex neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the widespread accumulation of alpha-synuclein (αSyn) protein aggregates. αSyn aggregation disrupts critical cellular processes, including synaptic function, mitochondrial integrity, and proteostasis, which [...] Read more.
Parkinson’s disease (PD) is a complex neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the widespread accumulation of alpha-synuclein (αSyn) protein aggregates. αSyn aggregation disrupts critical cellular processes, including synaptic function, mitochondrial integrity, and proteostasis, which culminate in neuronal cell death. Importantly, αSyn pathology extends beyond neurons—it also encompasses spreading throughout the neuronal environment and internalization by microglia and astrocytes. Once internalized, glia can act as neuroprotective scavengers, which limit the spread of αSyn. However, they can also become reactive, thereby contributing to neuroinflammation and the progression of PD. Recent advances in αSyn research have enabled the molecular diagnosis of PD and accelerated the development of targeted therapies. Nevertheless, despite more than two decades of research, the cellular function, aggregation mechanisms, and induction of cellular damage by αSyn remain incompletely understood. Unraveling the interplay between αSyn, neurons, and glia may provide insights into disease initiation and progression, which may bring us closer to exploring new effective therapeutic strategies. Herein, we provide an overview of recent studies emphasizing the multifaceted nature of αSyn and its impact on both neuron and glial cell damage. Full article
(This article belongs to the Special Issue The Structure and Function of Synuclein)
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16 pages, 357 KiB  
Review
The Mechanisms of the Roles of α-Synuclein, Amyloid-β, and Tau Protein in the Lewy Body Diseases: Pathogenesis, Early Detection, and Therapeutics
by Moeko Noguchi-Shinohara and Kenjiro Ono
Int. J. Mol. Sci. 2023, 24(12), 10215; https://doi.org/10.3390/ijms241210215 - 17 Jun 2023
Cited by 3 | Viewed by 1613
Abstract
Lewy body diseases (LBD) are pathologically defined as the accumulation of Lewy bodies composed of an aggregation of α-synuclein (αSyn). In LBD, not only the sole aggregation of αSyn but also the co-aggregation of amyloidogenic proteins, such as amyloid-β (Aβ) and tau, has [...] Read more.
Lewy body diseases (LBD) are pathologically defined as the accumulation of Lewy bodies composed of an aggregation of α-synuclein (αSyn). In LBD, not only the sole aggregation of αSyn but also the co-aggregation of amyloidogenic proteins, such as amyloid-β (Aβ) and tau, has been reported. In this review, the pathophysiology of co-aggregation of αSyn, Aβ, and tau protein and the advancement in imaging and fluid biomarkers that can detect αSyn and co-occurring Aβ and/or tau pathologies are discussed. Additionally, the αSyn-targeted disease-modifying therapies in clinical trials are summarized. Full article
(This article belongs to the Special Issue The Structure and Function of Synuclein)
19 pages, 1410 KiB  
Review
Unraveling the Complex Interplay between Alpha-Synuclein and Epigenetic Modification
by Naoto Sugeno and Takafumi Hasegawa
Int. J. Mol. Sci. 2023, 24(7), 6645; https://doi.org/10.3390/ijms24076645 - 2 Apr 2023
Viewed by 2103
Abstract
Alpha-synuclein (αS) is a small, presynaptic neuronal protein encoded by the SNCA gene. Point mutations and gene multiplication of SNCA cause rare familial forms of Parkinson’s disease (PD). Misfolded αS is cytotoxic and is a component of Lewy bodies, which are a pathological [...] Read more.
Alpha-synuclein (αS) is a small, presynaptic neuronal protein encoded by the SNCA gene. Point mutations and gene multiplication of SNCA cause rare familial forms of Parkinson’s disease (PD). Misfolded αS is cytotoxic and is a component of Lewy bodies, which are a pathological hallmark of PD. Because SNCA multiplication is sufficient to cause full-blown PD, gene dosage likely has a strong impact on pathogenesis. In sporadic PD, increased SNCA expression resulting from a minor genetic background and various environmental factors may contribute to pathogenesis in a complementary manner. With respect to genetic background, several risk loci neighboring the SNCA gene have been identified, and epigenetic alterations, such as CpG methylation and regulatory histone marks, are considered important factors. These alterations synergistically upregulate αS expression and some post-translational modifications of αS facilitate its translocation to the nucleus. Nuclear αS interacts with DNA, histones, and their modifiers to alter epigenetic status; thereby, influencing the stability of neuronal function. Epigenetic changes do not affect the gene itself but can provide an appropriate transcriptional response for neuronal survival through DNA methylation or histone modifications. As a new approach, publicly available RNA sequencing datasets from human midbrain-like organoids may be used to compare transcriptional responses through epigenetic alterations. This informatic approach combined with the vast amount of transcriptomics data will lead to the discovery of novel pathways for the development of disease-modifying therapies for PD. Full article
(This article belongs to the Special Issue The Structure and Function of Synuclein)
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