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α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration...
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α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration 2.0

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

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 8157

Special Issue Editors

Dr. François Ichas

E-Mail Website
Guest Editor
Institut des Maladies Neurodégénératives, CNRS et Université de Bordeaux, UMR 5293, Bordeaux, France
Interests: α-synuclein amyloids; fibril self-replication cycle; fragmentation; propagation; mutual interaction of α-synuclein amyloids and neurons; Parkinson’s disease; MSA
Special Issues, Collections and Topics in MDPI journals
Dr. John Woulfe

E-Mail Website
Guest Editor
Department of Pathology, The Ottawa Hospital, Civic Campus, 1053 Carling Avenue, Ottawa, ON K1Y 4E9, Canada
Interests: intranuclear inclusions; tubulin; Alzheimer's disease; Parkinson's disease; neuropathology; frontotemporal dementia

Special Issue Information

Dear Colleagues,

After the success of its first edition, it is our pleasure to propose a follow up to “α-Synuclein Amyloids and Parkinson’s Disease: On Growth, Spread, and Neurodegeneration”. For this second volume, we have teamed up to guest-edit a "neuropathology-oriented" issue. The over-arching objective is to reconcile the several discrepancies that exist between the various biological experimental models used to explore α-Synucleinopathies with the reality reflected in the molecular and cellular neuropathology of Parkinson's disease, MSA, and DLB. Indeed, the morphology as well as the cellular and anatomical localizations of α-Synuclein (α-Syn) inclusion bodies in human post-mortem brain are not accurately represented in a variety of cellular or animal models, suggesting that the latter lack veracity with respect to clinical and neuropathological reality. This represents a real problem for understanding and elucidating the true mechanisms underlying the α-Synucleinopathies, for challenging the genuine pathogenic role of α-Syn amyloid replication and spread (if any), and, ultimately, for the development of efficacious disease-modifying therapeutics. We hope that this volume will provide a springboard for a critical discussion of these issues.

Dr. François Ichas
Dr. John Woulfe
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

  • α-Synuclein
  • Parkinson’s disease
  • multiple system atrophy
  • dementia with Lewy bodies
  • Lewy bodies
  • Lewy neurites
  • cytoplasmic inclusions
  • nuclear inclusions
  • nucleus
  • amyloid fibrils
  • spread
  • prion-like
  • Braak’s hypothesis

Related Special Issues

Published Papers (2 papers)

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Research

26 pages, 5822 KiB  
Article
Protease-Sensitive and -Resistant Forms of Human and Murine Alpha-Synucleins in Distinct Brain Regions of Transgenic Mice (M83) Expressing the Human Mutated A53T Protein
by Dominique Bétemps, Jean-Noël Arsac, Simon Nicot, Dominique Canal, Habiba Tlili, Maxime Belondrade, Eric Morignat, Jérémy Verchère, Damien Gaillard, Lilian Bruyère-Ostells, Charly Mayran, Latifa Lakhdar, Daisy Bougard and Thierry Baron
Biomolecules 2023, 13(12), 1788; https://doi.org/10.3390/biom13121788 - 13 Dec 2023
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Abstract
Human neurodegenerative diseases associated with the misfolding of the alpha-synuclein (aS) protein (synucleinopathies) are similar to prion diseases to the extent that lesions are spread by similar molecular mechanisms. In a transgenic mouse model (M83) overexpressing a mutated (A53T) form of human aS, [...] Read more.
Human neurodegenerative diseases associated with the misfolding of the alpha-synuclein (aS) protein (synucleinopathies) are similar to prion diseases to the extent that lesions are spread by similar molecular mechanisms. In a transgenic mouse model (M83) overexpressing a mutated (A53T) form of human aS, we had previously found that Protein Misfolding Cyclic Amplification (PMCA) triggered the aggregation of aS, which is associated with a high resistance to the proteinase K (PK) digestion of both human and murine aS, a major hallmark of the disease-associated prion protein. In addition, PMCA was also able to trigger the aggregation of murine aS in C57Bl/6 mouse brains after seeding with sick M83 mouse brains. Here, we show that intracerebral inoculations of M83 mice with C57Bl/6-PMCA samples strikingly shortens the incubation period before the typical paralysis that develops in this transgenic model, demonstrating the pathogenicity of PMCA-aggregated murine aS. In the hind brain regions of these sick M83 mice containing lesions with an accumulation of aS phosphorylated at serine 129, aS also showed a high PK resistance in the N-terminal part of the protein. In contrast to M83 mice, old APPxM83 mice co-expressing human mutated amyloid precursor and presenilin 1 proteins were seen to have an aggregation of aS, especially in the cerebral cortex, hippocampus and striatum, which also contained the highest load of aS phosphorylated at serine 129. This was proven by three techniques: a Western blot analysis of PK-resistant aS; an ELISA detection of aS aggregates; or the identification of aggregates of aS using immunohistochemical analyses of cytoplasmic/neuritic aS deposits. The results obtained with the D37A6 antibody suggest a higher involvement of murine aS in APPxM83 mice than in M83 mice. Our study used novel tools for the molecular study of synucleinopathies, which highlight similarities with the molecular mechanisms involved in prion diseases. Full article
(This article belongs to the Special Issue α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration 2.0)
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17 pages, 5756 KiB  
Article
Oligodendrocytes Prune Axons Containing α-Synuclein Aggregates In Vivo: Lewy Neurites as Precursors of Glial Cytoplasmic Inclusions in Multiple System Atrophy?
by Francesco De Nuccio, Marianna Kashyrina, Francesca Serinelli, Florent Laferrière, Dario Domenico Lofrumento, Francesca De Giorgi and François Ichas
Biomolecules 2023, 13(2), 269; https://doi.org/10.3390/biom13020269 - 01 Feb 2023
Cited by 5 | Viewed by 6644
Abstract
α-Synucleinopathies are spreading neurodegenerative disorders characterized by the intracellular accumulation of insoluble aggregates populated by α-Synuclein (α-Syn) fibrils. In Parkinson’s disease (PD) and dementia with Lewy bodies, intraneuronal α-Syn aggregates are referred to as Lewy bodies in the somata and as Lewy neurites [...] Read more.
α-Synucleinopathies are spreading neurodegenerative disorders characterized by the intracellular accumulation of insoluble aggregates populated by α-Synuclein (α-Syn) fibrils. In Parkinson’s disease (PD) and dementia with Lewy bodies, intraneuronal α-Syn aggregates are referred to as Lewy bodies in the somata and as Lewy neurites in the neuronal processes. In multiple system atrophy (MSA) α-Syn aggregates are also found within mature oligodendrocytes (OLs) where they form Glial Cytoplasmic Inclusions (GCIs). However, the origin of GCIs remains enigmatic: (i) mature OLs do not express α-Syn, precluding the seeding and the buildup of inclusions and (ii) the artificial overexpression of α-Syn in OLs of transgenic mice results in a burden of soluble phosphorylated α-Syn but fails to form α-Syn fibrils. In contrast, mass spectrometry of α-Syn fibrillar aggregates from MSA patients points to the neuronal origin of the proteins intimately associated with the fibrils within the GCIs. This suggests that GCIs are preassembled in neurons and only secondarily incorporated into OLs. Interestingly, we recently isolated a synthetic human α-Syn fibril strain (1B fibrils) capable of seeding a type of neuronal inclusion observed early and specifically during MSA. Our goal was thus to investigate whether the neuronal α-Syn pathology seeded by 1B fibrils could eventually be transmitted to OLs to form GCIs in vivo. After confirming that mature OLs did not express α-Syn to detectable levels in the adult mouse brain, a series of mice received unilateral intra-striatal injections of 1B fibrils. The resulting α-Syn pathology was visualized using phospho-S129 α-Syn immunoreactivity (pSyn). We found that even though 1B fibrils were injected unilaterally, many pSyn-positive neuronal somas were present in layer V of the contralateral perirhinal cortex after 6 weeks. This suggested a fast retrograde spread of the pathology along the axons of crossing cortico-striatal neurons. We thus scrutinized the posterior limb of the anterior commissure, i.e., the myelinated interhemispheric tract containing the axons of these neurons: we indeed observed numerous pSyn-positive linear Lewy Neurites oriented parallel to the commissural axis, corresponding to axonal segments filled with aggregated α-Syn, with no obvious signs of OL α-Syn pathology at this stage. After 6 months however, the commissural Lewy neurites were no longer parallel but fragmented, curled up, sometimes squeezed in-between two consecutive OLs in interfascicular strands, or even engulfed inside OL perikarya, thus forming GCIs. We conclude that the 1B fibril strain can rapidly induce an α-Syn pathology typical of MSA in mice, in which the appearance of GCIs results from the pruning of diseased axonal segments containing aggregated α-Syn. Full article
(This article belongs to the Special Issue α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration 2.0)
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