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

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

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 46828

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Dr. François Ichas

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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
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Dear Colleagues,

Synuclein is an intrinsically disordered protein that oscillates between a variety of different conformations. In healthy neurons, α-synuclein (α-syn) is physiologically guided towards an alpha-helical form that oligomerizes at the surface of the neurosecretion vesicles to modulate neurotransmitter release. However, α-syn can also be incidentally diverted to self-assemble as fibrils adopting a cross-beta amyloid architecture. Due to the stability of the latter amyloid assemblies, this pathway hijacks the neuronal production of α-syn that ends up feeding the growth of pathological fibrillar inclusions. This process, which is prominent in Parkinson’s disease (PD), takes the form of Lewy bodies and Lewy neurites, and in many patients, it is associated with neurodegeneration and shows up in ever-increasing brain regions as the disease progresses. However, the relationship between the gradual spread of α-syn amyloid replication and neuronal death remains mysterious. Indeed, while α-syn fibrils could theoretically self-perpetuate their amyloid fold indefinitely by templated growth, this pathological process can proceed only as long as α-syn monomers are made available by the diseased host neurons. In other words, if growing α-syn amyloids were killing neurons too rapidly, this would dry out the supply of α-syn and both self-replication and spread would be damped and would abort.

If this holds true, then, it is tempting to speculate that only a subtle pathological state of equilibrium can account for the fact that the gradual worsening of both neurodegeneration and synucleinopathy exhibit parallel courses in numerous PD patients. Do certain of the α-syn fibrils intrinsic properties play a causal role in this equilibrium? Is this fibril strain-dependent? How do intermediary oligomers and secondary non-templated amyloid nucleations fit in this picture? Are phenomena of liquid-liquid phase separation involved? Do the mutations found in familial forms of PD displace this equilibrium? Are all neurons equal in that respect? Or finally, is the replication of α-syn amyloids that we identify with the spread of Lewy bodies simply a bystander phenomenon?

I hope that this Special Issue of Biomolecules will represent an opportunity to display and confront the current positions of the different schools of thoughts on these intriguing questions.

Dr. François Ichas
Guest Editor

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Keywords

α-synuclein
amyloids
nucleations
LLPS
fibril frangibility
disaggregases
Lewy bodies
neuronal susceptibility
neurodegeneration
Parkinson’s disease

Published Papers (11 papers)

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Research

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12 pages, 1953 KiB

Open AccessArticle

Comparative Analysis of the Relative Fragmentation Stabilities of Polymorphic Alpha-Synuclein Amyloid Fibrils

by Sarina Sanami, Tracey J. Purton, David P. Smith, Mick F. Tuite and Wei-Feng Xue

Biomolecules 2022, 12(5), 630; https://doi.org/10.3390/biom12050630 - 25 Apr 2022

Cited by 2 | Viewed by 2174

Abstract

The division of amyloid fibril particles through fragmentation is implicated in the progression of human neurodegenerative disorders such as Parkinson’s disease. Fragmentation of amyloid fibrils plays a crucial role in the propagation of the amyloid state encoded in their three-dimensional structures and may have an important role in the spreading of potentially pathological properties and phenotypes in amyloid-associated diseases. However, despite the mechanistic importance of fibril fragmentation, the relative stabilities of different types or different polymorphs of amyloid fibrils toward fragmentation remain to be quantified. We have previously developed an approach to compare the relative stabilities of different types of amyloid fibrils toward fragmentation. In this study, we show that controlled sonication, a widely used method of mechanical perturbation for amyloid seed generation, can be used as a form of mechanical perturbation for rapid comparative assessment of the relative fragmentation stabilities of different amyloid fibril structures. This approach is applied to assess the relative fragmentation stabilities of amyloid formed in vitro from wild type (WT) α-synuclein and two familial mutant variants of α-synuclein (A30P and A53T) that generate morphologically different fibril structures. Our results demonstrate that the fibril fragmentation stabilities of these different α-synuclein fibril polymorphs are all highly length dependent but distinct, with both A30P and A53T α-synuclein fibrils displaying increased resistance towards sonication-induced fibril fragmentation compared with WT α-synuclein fibrils. These conclusions show that fragmentation stabilities of different amyloid fibril polymorph structures can be diverse and suggest that the approach we report here will be useful in comparing the relative stabilities of amyloid fibril types or fibril polymorphs toward fragmentation under different biological conditions. Full article

(This article belongs to the Special Issue α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration)

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22 pages, 11126 KiB

Open AccessArticle

Neurons with Cat’s Eyes: A Synthetic Strain of α-Synuclein Fibrils Seeding Neuronal Intranuclear Inclusions

by Francesca De Giorgi, Muhammed Bilal Abdul-Shukkoor, Marianna Kashyrina, Leslie-Ann Largitte, Francesco De Nuccio, Brice Kauffmann, Alons Lends, Florent Laferrière, Sébastien Bonhommeau, Dario Domenico Lofrumento, Luc Bousset, Erwan Bezard, Thierry Buffeteau, Antoine Loquet and François Ichas

Biomolecules 2022, 12(3), 436; https://doi.org/10.3390/biom12030436 - 11 Mar 2022

Cited by 6 | Viewed by 5417

Abstract

The distinct neuropathological features of the different α-Synucleinopathies, as well as the diversity of the α-Synuclein (α-Syn) intracellular inclusion bodies observed in post mortem brain sections, are thought to reflect the strain diversity characterizing invasive α-Syn amyloids. However, this “one strain, one disease” view is still hypothetical, and to date, a possible disease-specific contribution of non-amyloid factors has not been ruled out. In Multiple System Atrophy (MSA), the buildup of α-Syn inclusions in oligodendrocytes seems to result from the terminal storage of α-Syn amyloid aggregates first pre-assembled in neurons. This assembly occurs at the level of neuronal cytoplasmic inclusions, and even earlier, within neuronal intranuclear inclusions (NIIs). Intriguingly, α-Syn NIIs are never observed in α-Synucleinopathies other than MSA, suggesting that these inclusions originate (i) from the unique molecular properties of the α-Syn fibril strains encountered in this disease, or alternatively, (ii) from other factors specifically dysregulated in MSA and driving the intranuclear fibrillization of α-Syn. We report the isolation and structural characterization of a synthetic human α-Syn fibril strain uniquely capable of seeding α-Syn fibrillization inside the nuclear compartment. In primary mouse cortical neurons, this strain provokes the buildup of NIIs with a remarkable morphology reminiscent of cat’s eye marbles (see video abstract). These α-Syn inclusions form giant patterns made of one, two, or three lentiform beams that span the whole intranuclear volume, pushing apart the chromatin. The input fibrils are no longer detectable inside the NIIs, where they become dominated by the aggregation of endogenous α-Syn. In addition to its phosphorylation at S129, α-Syn forming the NIIs acquires an epitope antibody reactivity profile that indicates its organization into fibrils, and is associated with the classical markers of α-Syn pathology p62 and ubiquitin. NIIs are also observed in vivo after intracerebral injection of the fibril strain in mice. Our data thus show that the ability to seed NIIs is a strain property that is integrally encoded in the fibril supramolecular architecture. Upstream alterations of cellular mechanisms are not required. In contrast to the lentiform TDP-43 NIIs, which are observed in certain frontotemporal dementias and which are conditional upon GRN or VCP mutations, our data support the hypothesis that the presence of α-Syn NIIs in MSA is instead purely amyloid-strain-dependent. Full article

(This article belongs to the Special Issue α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration)

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15 pages, 2601 KiB

Open AccessArticle

RT-QuIC Using C-Terminally Truncated α-Synuclein Forms Detects Differences in Seeding Propensity of Different Brain Regions from Synucleinopathies

by Ilaria Poggiolini, Daniel Erskine, Nishant N. Vaikath, Janarthanan Ponraj, Said Mansour, Christopher M. Morris and Omar M. A. El-Agnaf

Biomolecules 2021, 11(6), 820; https://doi.org/10.3390/biom11060820 - 31 May 2021

Cited by 13 | Viewed by 3877

Abstract

Aggregated α-synuclein (αSyn) protein is a core pathological feature of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Both PD and DLB demonstrate the presence of diverse intracellular α-synuclein (αSyn) species, including C-terminally truncated αSyn (C-αSyn), although it is unknown how C-αSyn species contribute to disease progression. Using recombinant C-αSyn and PD and DLB brain lysates as seeds in the real-time quaking-induced conversion (RT-QuIC) assay, we explored how C-αSyn may be involved in disease stratification. Comparing the seeding activity of aqueous-soluble fractions to detergent-soluble fractions, and using αSyn 1-130 as substrate for the RT-QuIC assay, the temporal cortex seeds differentiated PD and DLB from healthy controls. In contrast to the temporal cortex, where PD and DLB could not be distinguished, αSyn 1-130 seeded by the detergent-soluble fractions from the PD frontal cortex demonstrated greater seeding efficiency compared to the DLB frontal cortex. Moreover, proteinase K-resistant (PK^res) fragments from the RT-QuIC end products using C-αSyn 1-130 or C-αSyn 1-115 were more obvious in the frontal cortex compared to the temporal cortex. Morphological examinations of RT-QuIC end products showed differences in the size of the fibrils between C-αSyn 1-130 and C-αSyn 1-115, in agreement with the RT-QuIC results. These data show that C-αSyn species can distinguish PD from DLB and suggest diversity in αSyn species across these synucleinopathies, which could play a role in disease progression. Full article

(This article belongs to the Special Issue α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration)

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Review

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9 pages, 1147 KiB

Open AccessReview

α-Synuclein Fibrils as Penrose Machines: A Chameleon in the Gear

by Francesca De Giorgi, Vladimir N. Uversky and François Ichas

Biomolecules 2022, 12(4), 494; https://doi.org/10.3390/biom12040494 - 24 Mar 2022

Cited by 2 | Viewed by 3232

Abstract

In 1957, Lionel Penrose built the first man-made self-replicating mechanical device and illustrated its function in a series of machine prototypes, prefiguring our current view of the genesis and the proliferation of amyloid fibrils. He invented and demonstrated, with the help of his son Roger, the concepts that decades later, would become the fundamentals of prion and prion-like neurobiology: nucleation, seeding and conformational templating of monomers, linear polymer elongation, fragmentation, and spread. He published his premonitory discovery in a movie he publicly presented at only two conferences in 1958, a movie we thus reproduce here. By making a 30-year-jump in the early 90’s, we evoke the studies performed by Peter Lansbury and his group in which α-Synuclein (α-Syn) was for the first time (i) compared to a prion; (ii) shown to contain a fibrillization-prone domain capable of seeding its own assembly into fibrils; (iii) identified as an intrinsically disordered protein (IDP), and which, in the early 2000s, (iv) was described by one of us as a protein chameleon. We use these temporally distant breakthroughs to propose that the combination of the chameleon nature of α-Syn with the rigid gear of the Penrose machine is sufficient to account for a phenomenon that is of current interest: the emergence and the spread of a variety of α-Syn fibril strains in α-Synucleinopathies. Full article

(This article belongs to the Special Issue α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration)

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21 pages, 1919 KiB

Open AccessReview

Amyloid Fragmentation and Disaggregation in Yeast and Animals

by Vitaly V. Kushnirov, Alexander A. Dergalev and Alexander I. Alexandrov

Biomolecules 2021, 11(12), 1884; https://doi.org/10.3390/biom11121884 - 15 Dec 2021

Cited by 7 | Viewed by 3460

Abstract

Amyloids are filamentous protein aggregates that are associated with a number of incurable diseases, termed amyloidoses. Amyloids can also manifest as infectious or heritable particles, known as prions. While just one prion is known in humans and animals, more than ten prion amyloids have been discovered in fungi. The propagation of fungal prion amyloids requires the chaperone Hsp104, though in excess it can eliminate some prions. Even though Hsp104 acts to disassemble prion fibrils, at normal levels it fragments them into multiple smaller pieces, which ensures prion propagation and accelerates prion conversion. Animals lack Hsp104, but disaggregation is performed by the same complement of chaperones that assist Hsp104 in yeast—Hsp40, Hsp70, and Hsp110. Exogenous Hsp104 can efficiently cooperate with these chaperones in animals and promotes disaggregation, especially of large amyloid aggregates, which indicates its potential as a treatment for amyloid diseases. However, despite the significant effects, Hsp104 and its potentiated variants may be insufficient to fully dissolve amyloid. In this review, we consider chaperone mechanisms acting to disassemble heritable protein aggregates in yeast and animals, and their potential use in the therapy of human amyloid diseases. Full article

(This article belongs to the Special Issue α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration)

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35 pages, 6310 KiB

Open AccessReview

Structural and Functional Insights into α-Synuclein Fibril Polymorphism

by Surabhi Mehra, Laxmikant Gadhe, Riya Bera, Ajay Singh Sawner and Samir K. Maji

Biomolecules 2021, 11(10), 1419; https://doi.org/10.3390/biom11101419 - 28 Sep 2021

Cited by 34 | Viewed by 6572

Abstract

Abnormal accumulation of aggregated α-synuclein (α-Syn) is seen in a variety of neurodegenerative diseases, including Parkinson’s disease (PD), multiple system atrophy (MSA), dementia with Lewy body (DLB), Parkinson’s disease dementia (PDD), and even subsets of Alzheimer’s disease (AD) showing Lewy-body-like pathology. These synucleinopathies exhibit differences in their clinical and pathological representations, reminiscent of prion disorders. Emerging evidence suggests that α-Syn self-assembles and polymerizes into conformationally diverse polymorphs in vitro and in vivo, similar to prions. These α-Syn polymorphs arising from the same precursor protein may exhibit strain-specific biochemical properties and the ability to induce distinct pathological phenotypes upon their inoculation in animal models. In this review, we discuss clinical and pathological variability in synucleinopathies and several aspects of α-Syn fibril polymorphism, including the existence of high-resolution molecular structures and brain-derived strains. The current review sheds light on the recent advances in delineating the structure–pathogenic relationship of α-Syn and how diverse α-Syn molecular polymorphs contribute to the existing clinical heterogeneity in synucleinopathies. Full article

(This article belongs to the Special Issue α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration)

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18 pages, 873 KiB

Open AccessEditor’s ChoiceReview

Alpha-Synuclein and the Endolysosomal System in Parkinson’s Disease: Guilty by Association

by Maxime Teixeira, Razan Sheta, Walid Idi and Abid Oueslati

Biomolecules 2021, 11(9), 1333; https://doi.org/10.3390/biom11091333 - 09 Sep 2021

Cited by 20 | Viewed by 4287

Abstract

Abnormal accumulation of the protein α- synuclein (α-syn) into proteinaceous inclusions called Lewy bodies (LB) is the neuropathological hallmark of Parkinson’s disease (PD) and related disorders. Interestingly, a growing body of evidence suggests that LB are also composed of other cellular components such as cellular membrane fragments and vesicular structures, suggesting that dysfunction of the endolysosomal system might also play a role in LB formation and neuronal degeneration. Yet the link between α-syn aggregation and the endolysosomal system disruption is not fully elucidated. In this review, we discuss the potential interaction between α-syn and the endolysosomal system and its impact on PD pathogenesis. We propose that the accumulation of monomeric and aggregated α-syn disrupt vesicles trafficking, docking, and recycling, leading to the impairment of the endolysosomal system, notably the autophagy-lysosomal degradation pathway. Reciprocally, PD-linked mutations in key endosomal/lysosomal machinery genes (LRRK2, GBA, ATP13A2) also contribute to increasing α-syn aggregation and LB formation. Altogether, these observations suggest a potential synergistic role of α-syn and the endolysosomal system in PD pathogenesis and represent a viable target for the development of disease-modifying treatment for PD and related disorders. Full article

(This article belongs to the Special Issue α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration)

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20 pages, 2344 KiB

Open AccessEditor’s ChoiceReview

α-Synuclein Strains: Does Amyloid Conformation Explain the Heterogeneity of Synucleinopathies?

by Simon Oliver Hoppe, Gamze Uzunoğlu and Carmen Nussbaum-Krammer

Biomolecules 2021, 11(7), 931; https://doi.org/10.3390/biom11070931 - 23 Jun 2021

Cited by 14 | Viewed by 3634

Abstract

Synucleinopathies are a heterogeneous group of neurodegenerative diseases with amyloid deposits that contain the α-synuclein (SNCA/α-Syn) protein as a common hallmark. It is astonishing that aggregates of a single protein are able to give rise to a whole range of different disease manifestations. The prion strain hypothesis offers a possible explanation for this conundrum. According to this hypothesis, a single protein sequence is able to misfold into distinct amyloid structures that can cause different pathologies. In fact, a growing body of evidence suggests that conformationally distinct α-Syn assemblies might be the causative agents behind different synucleinopathies. In this review, we provide an overview of research on the strain hypothesis as it applies to synucleinopathies and discuss the potential implications for diagnostic and therapeutic purposes. Full article

(This article belongs to the Special Issue α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration)

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19 pages, 1004 KiB

Open AccessReview

Alpha-Synuclein and Mitochondrial Dysfunction in Parkinson’s Disease: The Emerging Role of VDAC

by Pierpaolo Risiglione, Federica Zinghirino, Maria Carmela Di Rosa, Andrea Magrì and Angela Messina

Biomolecules 2021, 11(5), 718; https://doi.org/10.3390/biom11050718 - 11 May 2021

Cited by 28 | Viewed by 4538

Abstract

Alpha-Synuclein (αSyn) is a protein whose function is still debated, as well as its role in modulation of mitochondrial function in both physiological and pathological conditions. Mitochondrial porins or Voltage-Dependent Anion Channel (VDAC) proteins are the main gates for ADP/ATP and various substrates towards the organelle. Furthermore, they act as a mitochondrial hub for many cytosolic proteins, including αSyn. This review analyzes the main aspects of αSyn-mitochondria interaction, focusing on the role of VDAC and its emerging involvement in the pathological processes. Full article

(This article belongs to the Special Issue α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration)

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9 pages, 942 KiB

Open AccessHypothesis

Production of Recombinant Alpha-Synuclein: Still No Standardized Protocol in Sight

by Mohammed Al-Azzani, Annekatrin König and Tiago Fleming Outeiro

Biomolecules 2022, 12(2), 324; https://doi.org/10.3390/biom12020324 - 18 Feb 2022

Cited by 5 | Viewed by 3240

Abstract

Synucleinopathies are a group of neurodegenerative diseases, characterized by the abnormal accumulation of the protein alpha-synuclein (aSyn). aSyn is an intrinsically disordered protein that can adopt different aggregation states, some of which may be associated with disease. Therefore, understanding the transitions between such aggregation states may be essential for deciphering the molecular underpinnings underlying synucleinopathies. Recombinant aSyn is routinely produced and purified from E. coli in many laboratories, and in vitro preparations of aSyn aggregated species became central for modeling neurodegeneration in cell and animal models. Thus, reproducibility and reliability of such studies largely depends on the purity and homogeneity of aSyn preparations across batches and between laboratories. A variety of different methods are in use to produce and purify aSyn, which we review in this commentary. We also show how extraction buffer composition can affect aSyn aggregation, emphasizing the importance of standardizing protocols to ensure reproducibility between different laboratories and studies, which are essential for advancing the field. Full article

(This article belongs to the Special Issue α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration)

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8 pages, 240 KiB

Open AccessOpinion

How Lazy Reading and Semantic Sloppiness May Harm Progress in Synucleinopathy Research

by Erwan Bezard

Biomolecules 2022, 12(2), 228; https://doi.org/10.3390/biom12020228 - 28 Jan 2022

Cited by 4 | Viewed by 3237

Abstract

While confronted with the increasing complexity of the neurobiology of Parkinson’s disease (PD), we face the ever-increasing sloppiness of the conceptual definitions associated with poor methodological characterizations and the use of unacknowledged proxies, all of which are harmful contributors to the overall slow progress of PD research. In this opinion paper, I share part of my frustration, acknowledge how I participate in this trend, and propose a simple remedy. Fighting against semantic or conceptual sloppiness is of paramount importance, notably for the benefit of newcomers to the field who otherwise would take for granted the classic assertions found ad nauseam in the literature. Full article

(This article belongs to the Special Issue α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration)

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