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Biomolecules
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Molecular Mechanisms of Alpha-Synuclein in Parkinson's Disease and Other Synucleinopathies
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Molecular Mechanisms of Alpha-Synuclein in Parkinson's Disease and Other Synucleinopathies

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

Deadline for manuscript submissions: closed (30 March 2024) | Viewed by 7088

Special Issue Editors

Prof. Dr. Felix Javier Jiménez Jiménez

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Guest Editor
Department of Neurology, Hospital Universitario del Sureste, Ronda del Sur 10, E28500 Arganda del Rey, Madrid, Spain
Interests: movement disorders; Parkinson’s disease; neurodegenerative diseases; restless leg syndrome; genetics; biochemistry; risk factors
Special Issues, Collections and Topics in MDPI journals
Dr. Iván Martínez-Valbuena

E-Mail Website
Guest Editor
Tanz Centre for Research in Neurodegenerative Disease and The Rossy Program in Progressive Supranuclear Palsy, Krembil Discovery Tower, University of Toronto and University Health Network, 60 Leonard Ave Toronto On, Toronto, ON M5T 0S8, Canada
Interests: neurodegenerative diseases; neuropathology; seeding assays; Parkinson’s disease; multiple-system atrophy; biochemistry; alpha synuclein
Dr. Diego Santos-García

E-Mail Website
Guest Editor
Department of Neurology, Hospital Universitario de A Coruña (HUAC), Complejo Hospitalario Universitario de A Coruña (CHUAC), C/As Xubias 84, 15006 A Coruña, Spain
Interests: movement disorders; Parkinson’s disease; neurodegenerative diseases; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Twenty-five years ago, researchers discovered that mutations in the alpha-synuclein (SNCA or PARK1) gene are responsible for an autosomal dominant form of Parkinson’s disease (PD), and that alpha-synuclein protein is an important component of Lewy bodies (the hallmark of PD). Thereafter, it was discovered that alpha-synuclein is accumulated in Lewy bodies in other disorders such as PD with dementia (PDD) and dementia with Lewy bodies (DLB), and in the form of glial cytoplasmatic inclusions in multiple-system atrophy (MSA). The term “synucleinopathies” was coined to encompass PD, PDD, DLB, and MSA. Alpha-synuclein is expressed not only in the central nervous system (CNS), but also in some peripheral diseases, and is a reliable biological marker for these diseases. Since 1997, approximately 12,000 articles have been published regarding alpha-synuclein, but the role of this protein in PD and other synucleinopathies is not yet fully understood. For this reason, we propose a Special Issue on the molecular mechanisms of alpha-synuclein in PD and other synucleinopathies and welcome submissions on this this topic.

Prof. Dr. Felix Javier Jiménez Jiménez
Dr. Iván Martínez-Valbuena
Dr. Diego Santos-García
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

  • alpha-synuclein
  • molecular mechanisms
  • movement disorders
  • Parkinson’s disease
  • dementia with lewy bodies
  • multiple-system atrophy
  • biomarkers
  • biochemistry
  • risk factors

Published Papers (4 papers)

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Research

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19 pages, 6514 KiB  
Article
Aggregation-Inhibiting scFv-Based Therapies Protect Mice against AAV1/2-Induced A53T-α-Synuclein Overexpression
by Benjamin W. Schlichtmann, Bharathi N. Palanisamy, Emir Malovic, Susheel K. Nethi, Piyush Padhi, Monica Hepker, Joseph Wurtz, Manohar John, Bhupal Ban, Vellareddy Anantharam, Anumantha G. Kanthasamy, Balaji Narasimhan and Surya K. Mallapragada
Biomolecules 2023, 13(8), 1203; https://doi.org/10.3390/biom13081203 - 31 Jul 2023
Cited by 1 | Viewed by 1249
Abstract
To date, there is no cure for Parkinson’s disease (PD). There is a pressing need for anti-neurodegenerative therapeutics that can slow or halt PD progression by targeting underlying disease mechanisms. Specifically, preventing the build-up of alpha-synuclein (αSyn) and its aggregated and mutated forms [...] Read more.
To date, there is no cure for Parkinson’s disease (PD). There is a pressing need for anti-neurodegenerative therapeutics that can slow or halt PD progression by targeting underlying disease mechanisms. Specifically, preventing the build-up of alpha-synuclein (αSyn) and its aggregated and mutated forms is a key therapeutic target. In this study, an adeno-associated viral vector loaded with the A53T gene mutation was used to induce rapid αSyn-associated PD pathogenesis in C57BL/6 mice. We tested the ability of a novel therapeutic, a single chain fragment variable (scFv) antibody with specificity only for pathologic forms of αSyn, to protect against αSyn-induced neurodegeneration, after unilateral viral vector injection in the substantia nigra. Additionally, polyanhydride nanoparticles, which provide sustained release of therapeutics with dose-sparing properties, were used as a delivery platform for the scFv. Through bi-weekly behavioral assessments and across multiple post-mortem immunochemical analyses, we found that the scFv-based therapies allowed the mice to recover motor activity and reduce overall αSyn expression in the substantia nigra. In summary, these novel scFv-based therapies, which are specific exclusively for pathological aggregates of αSyn, show early promise in blocking PD progression in a surrogate mouse PD model. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Alpha-Synuclein in Parkinson's Disease and Other Synucleinopathies)
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19 pages, 4790 KiB  
Article
Disease-Specific α-Synuclein Seeding in Lewy Body Disease and Multiple System Atrophy Are Preserved in Formaldehyde-Fixed Paraffin-Embedded Human Brain
by Ain Kim, Ivan Martinez-Valbuena, Jun Li, Anthony E. Lang and Gabor G. Kovacs
Biomolecules 2023, 13(6), 936; https://doi.org/10.3390/biom13060936 - 02 Jun 2023
Cited by 2 | Viewed by 2134
Abstract
Recent studies have been able to detect α-synuclein (αSyn) seeding in formaldehyde-fixed paraffin-embedded (FFPE) tissues from patients with synucleinopathies using seed amplification assays (SAAs), but with relatively low sensitivity due to limited protein extraction efficiency. With the aim of introducing an alternative option [...] Read more.
Recent studies have been able to detect α-synuclein (αSyn) seeding in formaldehyde-fixed paraffin-embedded (FFPE) tissues from patients with synucleinopathies using seed amplification assays (SAAs), but with relatively low sensitivity due to limited protein extraction efficiency. With the aim of introducing an alternative option to frozen tissues, we developed a streamlined protein extraction protocol for evaluating disease-specific seeding in FFPE human brain. We evaluated the protein extraction efficiency of different tissue preparations, deparaffinizations, and protein extraction buffers using formaldehyde-fixed and FFPE tissue of a single Lewy body disease (LBD) subject. Alternatively, we incorporated heat-induced antigen retrieval and dissociation using a commercially available kit. Our novel protein extraction protocol has been optimized to work with 10 sections of 4.5-µm-thickness or 2-mm-diameter micro-punch of FFPE tissue that can be used to seed SAAs. We demonstrated that extracted proteins from FFPE still preserve seeding potential and further show disease-specific seeding in LBD and multiple system atrophy. To the best of our knowledge, our study is the first to recapitulate disease-specific αSyn seeding behaviour in FFPE human brain. Our findings open new perspectives in re-evaluating archived human brain tissue, extending the disease-specific seeding assays to larger cohorts to facilitate molecular subtyping of synucleinopathies. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Alpha-Synuclein in Parkinson's Disease and Other Synucleinopathies)
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Review

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20 pages, 2363 KiB  
Review
The Effects of Lipids on α-Synuclein Aggregation In Vitro
by Jennifer Ramirez, Samantha X. Pancoe, Elizabeth Rhoades and E. James Petersson
Biomolecules 2023, 13(10), 1476; https://doi.org/10.3390/biom13101476 - 02 Oct 2023
Viewed by 1438
Abstract
The small neuronal protein α-synuclein (αS) is found in pre-synaptic terminals and plays a role in vesicle recycling and neurotransmission. Fibrillar aggregates of αS are the hallmark of Parkinson’s disease and related neurodegenerative disorders. In both health and disease, interactions with lipids influence [...] Read more.
The small neuronal protein α-synuclein (αS) is found in pre-synaptic terminals and plays a role in vesicle recycling and neurotransmission. Fibrillar aggregates of αS are the hallmark of Parkinson’s disease and related neurodegenerative disorders. In both health and disease, interactions with lipids influence αS’s structure and function, prompting much study of the effects of lipids on αS aggregation. A comprehensive collection (126 examples) of aggregation rate data for various αS/lipid combinations was presented, including combinations of lipid variations and mutations or post-translational modifications of αS. These data were interpreted in terms of lipid structure to identify general trends. These tabulated data serve as a resource for the community to help in the interpretation of aggregation experiments with lipids and to be potentially used as inputs for computational models of lipid effects on aggregation. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Alpha-Synuclein in Parkinson's Disease and Other Synucleinopathies)
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34 pages, 560 KiB  
Review
Alpha-Synuclein in Peripheral Tissues as a Possible Marker for Neurological Diseases and Other Medical Conditions
by Félix Javier Jiménez-Jiménez, Hortensia Alonso-Navarro, Elena García-Martín, Diego Santos-García, Iván Martínez-Valbuena and José A. G. Agúndez
Biomolecules 2023, 13(8), 1263; https://doi.org/10.3390/biom13081263 - 18 Aug 2023
Cited by 4 | Viewed by 1459
Abstract
The possible usefulness of alpha-synuclein (aSyn) determinations in peripheral tissues (blood cells, salivary gland biopsies, olfactory mucosa, digestive tract, skin) and in biological fluids, except for cerebrospinal fluid (serum, plasma, saliva, feces, urine), as a marker of several diseases, has been the subject [...] Read more.
The possible usefulness of alpha-synuclein (aSyn) determinations in peripheral tissues (blood cells, salivary gland biopsies, olfactory mucosa, digestive tract, skin) and in biological fluids, except for cerebrospinal fluid (serum, plasma, saliva, feces, urine), as a marker of several diseases, has been the subject of numerous publications. This narrative review summarizes data from studies trying to determine the role of total, oligomeric, and phosphorylated aSyn determinations as a marker of various diseases, especially PD and other alpha-synucleinopathies. In summary, the results of studies addressing the determinations of aSyn in its different forms in peripheral tissues (especially in platelets, skin, and digestive tract, but also salivary glands and olfactory mucosa), in combination with other potential biomarkers, could be a useful tool to discriminate PD from controls and from other causes of parkinsonisms, including synucleinopathies. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Alpha-Synuclein in Parkinson's Disease and Other Synucleinopathies)
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