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Open AccessArticle

Toxic Oligomeric Alpha-Synuclein Variants Present in Human Parkinson’s Disease Brains Are Differentially Generated in Mammalian Cell Models

by Wei Xin, Sharareh Emadi, Stephanie Williams, Qiang Liu, Philip Schulz, Ping He, Now Bahar Alam, Jie Wu and Michael R. Sierks

Biomolecules 2015, 5(3), 1634-1651; https://doi.org/10.3390/biom5031634 - 22 Jul 2015

Cited by 34 | Viewed by 8823

Abstract

Misfolding and aggregation of α-synuclein into toxic soluble oligomeric α-synuclein aggregates has been strongly correlated with the pathogenesis of Parkinson’s disease (PD). Here, we show that two different morphologically distinct oligomeric α-synuclein aggregates are present in human post-mortem PD brain tissue and are [...] Read more.

Misfolding and aggregation of α-synuclein into toxic soluble oligomeric α-synuclein aggregates has been strongly correlated with the pathogenesis of Parkinson’s disease (PD). Here, we show that two different morphologically distinct oligomeric α-synuclein aggregates are present in human post-mortem PD brain tissue and are responsible for the bulk of α-synuclein induced toxicity in brain homogenates from PD samples. Two antibody fragments that selectively bind the different oligomeric α-synuclein variants block this α-synuclein induced toxicity and are useful tools to probe how various cell models replicate the α-synuclein aggregation pattern of human PD brain. Using these reagents, we show that mammalian cell type strongly influences α-synuclein aggregation, where neuronal cells best replicate the PD brain α-synuclein aggregation profile. Overexpression of α-synuclein in the different cell lines increased protein aggregation but did not alter the morphology of the oligomeric aggregates generated. Differentiation of the neuronal cells into a cholinergic-like or dopaminergic-like phenotype increased the levels of oligomeric α-synuclein where the aggregates were localized in cell neurites and cell bodies. Full article

(This article belongs to the Special Issue Exploring the Mechanisms by which α-Synuclein Kills Cells in Parkinson Disease)

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Open AccessArticle

Effects of Trehalose on Thermodynamic Properties of Alpha-synuclein Revealed through Synchrotron Radiation Circular Dichroism

by Paolo Ruzza, Rohanah Hussain, Barbara Biondi, Andrea Calderan, Isabella Tessari, Luigi Bubacco and Giuliano Siligardi

Biomolecules 2015, 5(2), 724-734; https://doi.org/10.3390/biom5020724 - 4 May 2015

Cited by 29 | Viewed by 8428

Abstract

Many neurodegenerative diseases, including Huntington’s, Alzheimer’s and Parkinson’s diseases, are characterized by protein misfolding and aggregation. The capability of trehalose to interfere with protein misfolding and aggregation has been recently evaluated by several research groups. In the present work, we studied, by means [...] Read more.

Many neurodegenerative diseases, including Huntington’s, Alzheimer’s and Parkinson’s diseases, are characterized by protein misfolding and aggregation. The capability of trehalose to interfere with protein misfolding and aggregation has been recently evaluated by several research groups. In the present work, we studied, by means of synchrotron radiation circular dichroism (SRCD) spectroscopy, the dose-effect of trehalose on α-synuclein conformation and/or stability to probe the capability of this osmolyte to interfere with α-synuclein’s aggregation. Our study indicated that a low trehalose concentration stabilized α-synuclein folding much better than at high concentration by blocking in vitro α-synuclein’s polymerisation. These results suggested that trehalose could be associated with other drugs leading to a new approach for treating Parkinson’s and other brain-related diseases. Full article

(This article belongs to the Special Issue Exploring the Mechanisms by which α-Synuclein Kills Cells in Parkinson Disease)

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Open AccessArticle

α-Synuclein-Induced Synapse Damage in Cultured Neurons Is Mediated by Cholesterol-Sensitive Activation of Cytoplasmic Phospholipase A₂

by Clive Bate and Alun Williams

Biomolecules 2015, 5(1), 178-193; https://doi.org/10.3390/biom5010178 - 9 Mar 2015

Cited by 25 | Viewed by 6568

Abstract

The accumulation of aggregated forms of the α-synuclein (αSN) is associated with the pathogenesis of Parkinson’s disease (PD) and Dementia with Lewy Bodies. The loss of synapses is an important event in the pathogenesis of these diseases. Here we show that aggregated recombinant [...] Read more.

The accumulation of aggregated forms of the α-synuclein (αSN) is associated with the pathogenesis of Parkinson’s disease (PD) and Dementia with Lewy Bodies. The loss of synapses is an important event in the pathogenesis of these diseases. Here we show that aggregated recombinant human αSN, but not βSN, triggered synapse damage in cultured neurons as measured by the loss of synaptic proteins. Pre-treatment with the selective cytoplasmic phospholipase A₂ (cPLA₂) inhibitors AACOCF₃ and MAFP protected neurons against αSN-induced synapse damage. Synapse damage was associated with the αSN-induced activation of synaptic cPLA₂ and the production of prostaglandin E₂. The activation of cPLA₂ is the first step in the generation of platelet-activating factor (PAF) and PAF receptor antagonists (ginkgolide B or Hexa-PAF) also protect neurons against αSN-induced synapse damage. αSN-induced synapse damage was also reduced in neurons pre-treated with the cholesterol synthesis inhibitor (squalestatin). These results are consistent with the hypothesis that αSN triggered synapse damage via hyperactivation of cPLA₂. They also indicate that αSN-induced activation of cPLA₂ is influenced by the cholesterol content of membranes. Inhibitors of this pathway that can cross the blood brain barrier may protect against the synapse damage seen during PD. Full article

(This article belongs to the Special Issue Exploring the Mechanisms by which α-Synuclein Kills Cells in Parkinson Disease)

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Review

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Open AccessReview

Αlpha-Synuclein as a Mediator in the Interplay between Aging and Parkinson’s Disease

by Wojciech Bobela, Patrick Aebischer and Bernard Laurent Schneider

Biomolecules 2015, 5(4), 2675-2700; https://doi.org/10.3390/biom5042675 - 16 Oct 2015

Cited by 51 | Viewed by 11229

Abstract

Accumulation and misfolding of the alpha-synuclein protein are core mechanisms in the pathogenesis of Parkinson’s disease. While the normal function of alpha-synuclein is mainly related to the control of vesicular neurotransmission, its pathogenic effects are linked to various cellular functions, which include mitochondrial [...] Read more.

Accumulation and misfolding of the alpha-synuclein protein are core mechanisms in the pathogenesis of Parkinson’s disease. While the normal function of alpha-synuclein is mainly related to the control of vesicular neurotransmission, its pathogenic effects are linked to various cellular functions, which include mitochondrial activity, as well as proteasome and autophagic degradation of proteins. Remarkably, these functions are also affected when the renewal of macromolecules and organelles becomes impaired during the normal aging process. As aging is considered a major risk factor for Parkinson’s disease, it is critical to explore its molecular and cellular implications in the context of the alpha-synuclein pathology. Here, we discuss similarities and differences between normal brain aging and Parkinson’s disease, with a particular emphasis on the nigral dopaminergic neurons, which appear to be selectively vulnerable to the combined effects of alpha-synuclein and aging. Full article

(This article belongs to the Special Issue Exploring the Mechanisms by which α-Synuclein Kills Cells in Parkinson Disease)

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Open AccessReview

Direct and/or Indirect Roles for SUMO in Modulating Alpha-Synuclein Toxicity

by Shamini Vijayakumaran, Mathew B. Wong, Helma Antony and Dean L. Pountney

Biomolecules 2015, 5(3), 1697-1716; https://doi.org/10.3390/biom5031697 - 24 Jul 2015

Cited by 27 | Viewed by 9186

Abstract

α-Synuclein inclusion bodies are a pathological hallmark of several neurodegenerative diseases, including Parkinson’s disease, and contain aggregated α-synuclein and a variety of recruited factors, including protein chaperones, proteasome components, ubiquitin and the small ubiquitin-like modifier, SUMO-1. Cell culture and animal model studies suggest [...] Read more.

α-Synuclein inclusion bodies are a pathological hallmark of several neurodegenerative diseases, including Parkinson’s disease, and contain aggregated α-synuclein and a variety of recruited factors, including protein chaperones, proteasome components, ubiquitin and the small ubiquitin-like modifier, SUMO-1. Cell culture and animal model studies suggest that misfolded, aggregated α-synuclein is actively translocated via the cytoskeletal system to a region of the cell where other factors that help to lessen the toxic effects can also be recruited. SUMO-1 covalently conjugates to various intracellular target proteins in a way analogous to ubiquitination to alter cellular distribution, function and metabolism and also plays an important role in a growing list of cellular pathways, including exosome secretion and apoptosis. Furthermore, SUMO-1 modified proteins have recently been linked to cell stress responses, such as oxidative stress response and heat shock response, with increased SUMOylation being neuroprotective in some cases. Several recent studies have linked SUMOylation to the ubiquitin-proteasome system, while other evidence implicates the lysosomal pathway. Other reports depict a direct mechanism whereby sumoylation reduced the aggregation tendency of α-synuclein, and reduced the toxicity. However, the precise role of SUMO-1 in neurodegeneration remains unclear. In this review, we explore the potential direct or indirect role(s) of SUMO-1 in the cellular response to misfolded α-synuclein in neurodegenerative disorders. Full article

(This article belongs to the Special Issue Exploring the Mechanisms by which α-Synuclein Kills Cells in Parkinson Disease)

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Open AccessReview

Is Cell Death Primary or Secondary in the Pathophysiology of Idiopathic Parkinson’s Disease?

by Walter J. Schulz-Schaeffer

Biomolecules 2015, 5(3), 1467-1479; https://doi.org/10.3390/biom5031467 - 16 Jul 2015

Cited by 42 | Viewed by 20289

Abstract

Currently, the pathophysiology of idiopathic Parkinson’s disease is explained by a loss of mainly dopaminergic nerve cells that causes a neurotransmitter deficiency. In the final stage of the disease, there is a marked loss of neurons in the substantia nigra. In addition, Lewy [...] Read more.

Currently, the pathophysiology of idiopathic Parkinson’s disease is explained by a loss of mainly dopaminergic nerve cells that causes a neurotransmitter deficiency. In the final stage of the disease, there is a marked loss of neurons in the substantia nigra. In addition, Lewy bodies can be found in some of the remaining neurons, which serve as the pathological hallmark of the disease. These Lewy bodies are composed mainly of aggregated α-synuclein, a physiological presynaptic protein. Lewy bodies were thought to be the pathophysiologically relevant form of α-synuclein because their appearance coincided with neuron loss in the substantia nigra. In consequence, neuron loss was thought to be the primary step in the neurodegeneration in Parkinson’s disease. On the other hand, the clinical syndrome suggests a synaptic disorder. If α-synuclein aggregation was causally linked to the pathophysiology of disease, α-synuclein pathology should be found at the synapse. As recently demonstrated, one to two orders of magnitude more α-synuclein aggregates are present in presynaptic terminals than in Lewy bodies or Lewy neurites. Degeneration of dendritic spines associated with synaptic α-synuclein aggregates has been shown to occur in human disease. In experiments, using transgenic mice or cell cultures, mild (two- to three-fold) overexpression of α-synuclein caused an altered vesicle turnover and led to a reduction in neurotransmitter release. Different approaches linked these alterations to presynaptic aggregation of α-synuclein. These findings may fundamentally change the pathophysiological concept of Parkinson’s disease: not nerve cell loss, but the synaptic dysfunction of still existing nerve cells should become the focus of attention. From recent findings, it is quite evident that the death of dopaminergic neurons is a secondary event in the pathophysiology of Parkinson’s disease. Full article

(This article belongs to the Special Issue Exploring the Mechanisms by which α-Synuclein Kills Cells in Parkinson Disease)

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Open AccessReview

Synthetic Proteins and Peptides for the Direct Interrogation of α-Synuclein Posttranslational Modifications

by Matthew R. Pratt, Tharindumala Abeywardana and Nicholas P. Marotta

Biomolecules 2015, 5(3), 1210-1227; https://doi.org/10.3390/biom5031210 - 25 Jun 2015

Cited by 12 | Viewed by 7668

Abstract

α-Synuclein is the aggregation-prone protein associated with Parkinson’s disease (PD) and related neurodegenerative diseases. Complicating both its biological functions and toxic aggregation are a variety of posttranslational modifications. These modifications have the potential to either positively or negatively affect α-synuclein aggregation, raising the [...] Read more.

α-Synuclein is the aggregation-prone protein associated with Parkinson’s disease (PD) and related neurodegenerative diseases. Complicating both its biological functions and toxic aggregation are a variety of posttranslational modifications. These modifications have the potential to either positively or negatively affect α-synuclein aggregation, raising the possibility that the enzymes that add or remove these modifications could be therapeutic targets in PD. Synthetic protein chemistry is uniquely positioned to generate site-specifically and homogeneously modified proteins for biochemical study. Here, we review the application of synthetic peptides and proteins towards understanding the effects of α-synuclein posttranslational modifications. Full article

(This article belongs to the Special Issue Exploring the Mechanisms by which α-Synuclein Kills Cells in Parkinson Disease)

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Open AccessReview

Interaction between Neuromelanin and Alpha-Synuclein in Parkinson’s Disease

by Shengli Xu and Piu Chan

Biomolecules 2015, 5(2), 1122-1142; https://doi.org/10.3390/biom5021122 - 5 Jun 2015

Cited by 35 | Viewed by 12333

Abstract

Parkinson’s disease (PD) is a very common neurodegenerative disorder characterized by the accumulation of α-synuclein (α-syn) into Lewy body (LB) inclusions and the loss of neuronmelanin (NM) containing dopamine (DA) neurons in the substantia nigra (SN). Pathological α-syn and NM are two prominent [...] Read more.

Parkinson’s disease (PD) is a very common neurodegenerative disorder characterized by the accumulation of α-synuclein (α-syn) into Lewy body (LB) inclusions and the loss of neuronmelanin (NM) containing dopamine (DA) neurons in the substantia nigra (SN). Pathological α-syn and NM are two prominent hallmarks in this selective and progressive neurodegenerative disease. Pathological α-syn can induce dopaminergic neuron death by various mechanisms, such as inducing oxidative stress and inhibiting protein degradation systems. Therefore, to explore the factors that trigger α-syn to convert from a non-toxic protein to toxic one is a pivotal question to clarify the mechanisms of PD pathogenesis. Many triggers for pathological α-syn aggregation have been identified, including missense mutations in the α-syn gene, higher concentration, and posttranslational modifications of α-Syn. Recently, the role of NM in inducing α-syn expression and aggregation has been suggested as a mechanism for this pigment to modulate neuronal vulnerability in PD. NM may be responsible for PD and age-associated increase and aggregation in α-syn. Here, we reviewed our previous study and other recent findings in the area of interaction between NM and α-syn. Full article

(This article belongs to the Special Issue Exploring the Mechanisms by which α-Synuclein Kills Cells in Parkinson Disease)

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Open AccessReview

Role of α- and β-Synucleins in the Axonal Pathology of Parkinson’s Disease and Related Synucleinopathies

by Akio Sekigawa, Yoshiki Takamatsu, Kazunari Sekiyama and Makoto Hashimoto

Biomolecules 2015, 5(2), 1000-1011; https://doi.org/10.3390/biom5021000 - 19 May 2015

Cited by 11 | Viewed by 10715

Abstract

Axonal swellings are histological hallmarks of axonopathies in various types of disorders in the central nervous system, including neurodegenerative diseases. Given the pivotal role of axonopathies during the early phase of neurodegenerative process, axonal swellings may be good models which may provide some [...] Read more.

Axonal swellings are histological hallmarks of axonopathies in various types of disorders in the central nervous system, including neurodegenerative diseases. Given the pivotal role of axonopathies during the early phase of neurodegenerative process, axonal swellings may be good models which may provide some clues for early pathogenesis of α-synucleinopathies, including Parkinson’s disease and dementia with Lewy bodies (DLB). In this mini-review, such a possibility is discussed based on our recent studies as well as other accumulating studies. Consistent with the current view that dysfunction in the autophagy-lysosomal system may play a major role in the formation of axonal swellings, our studies showed globule, small axonal swellings, derived from transgenic mice expressing either human wild-type α-synuclein (αS-globule) or DLB-linked P123H β-synuclein (βS-globule), contained autophagosome-like membranes. However, other pathological features, such as abnormal mitochondria, enhanced oxidative stress and LRRK2 accumulation, were observed in the αS-globules, but not in the βS-globules. Collectively, it is predicted that αS and βS may be involved in axonopathies through similar but distinct mechanisms, and thus, contribute to diverse axonal pathologies. Further studies of the axonal swellings may lead to elucidating the pathogenic mechanism of early α-synucleinopathies and illuminating a strategy for a disease-modifying therapy against these devastating disorders. Full article

(This article belongs to the Special Issue Exploring the Mechanisms by which α-Synuclein Kills Cells in Parkinson Disease)

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Open AccessReview

Mechanisms of Alpha-Synuclein Action on Neurotransmission: Cell-Autonomous and Non-Cell Autonomous Role

by Marco Emanuele and Evelina Chieregatti

Biomolecules 2015, 5(2), 865-892; https://doi.org/10.3390/biom5020865 - 13 May 2015

Cited by 43 | Viewed by 14314

Abstract

Mutations and duplication/triplication of the alpha-synuclein (αSyn)-coding gene have been found to cause familial Parkinson’s disease (PD), while genetic polymorphisms in the region controlling the expression level and stability of αSyn have been identified as risk factors for idiopathic PD, pointing to the [...] Read more.

Mutations and duplication/triplication of the alpha-synuclein (αSyn)-coding gene have been found to cause familial Parkinson’s disease (PD), while genetic polymorphisms in the region controlling the expression level and stability of αSyn have been identified as risk factors for idiopathic PD, pointing to the importance of wild-type (wt) αSyn dosage in the disease. Evidence that αSyn is present in the cerebrospinal fluid and interstitial brain tissue and that healthy neuronal grafts transplanted into PD patients often degenerate suggests that extracellularly-released αSyn plays a role in triggering the neurodegenerative process. αSyn’s role in neurotransmission has been shown in various cell culture models in which the protein was upregulated or deleted and in knock out and transgenic animal, with different results on αSyn’s effect on synaptic vesicle pool size and mobilization, αSyn being proposed as a negative or positive regulator of neurotransmitter release. In this review, we discuss the effect of αSyn on pre- and post-synaptic compartments in terms of synaptic vesicle trafficking, calcium entry and channel activity, and we focus on the process of exocytosis and internalization of αSyn and on the spreading of αSyn-driven effects due to the presence of the protein in the extracellular milieu. Full article

(This article belongs to the Special Issue Exploring the Mechanisms by which α-Synuclein Kills Cells in Parkinson Disease)

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Open AccessReview

Sirtuins and Proteolytic Systems: Implications for Pathogenesis of Synucleinopathies

by Belém Sampaio-Marques and Paula Ludovico

Biomolecules 2015, 5(2), 735-757; https://doi.org/10.3390/biom5020735 - 4 May 2015

Cited by 11 | Viewed by 7422

Abstract

Insoluble and fibrillar forms of α-synuclein are the major components of Lewy bodies, a hallmark of several sporadic and inherited neurodegenerative diseases known as synucleinopathies. α-Synuclein is a natural unfolded and aggregation-prone protein that can be degraded by the ubiquitin-proteasomal system and the [...] Read more.

Insoluble and fibrillar forms of α-synuclein are the major components of Lewy bodies, a hallmark of several sporadic and inherited neurodegenerative diseases known as synucleinopathies. α-Synuclein is a natural unfolded and aggregation-prone protein that can be degraded by the ubiquitin-proteasomal system and the lysosomal degradation pathways. α-Synuclein is a target of the main cellular proteolytic systems, but it is also able to alter their function further, contributing to the progression of neurodegeneration. Aging, a major risk for synucleinopathies, is associated with a decrease activity of the proteolytic systems, further aggravating this toxic looping cycle. Here, the current literature on the basic aspects of the routes for α-synuclein clearance, as well as the consequences of the proteolytic systems collapse, will be discussed. Finally, particular focus will be given to the sirtuins’s role on proteostasis regulation, since their modulation emerged as a promising therapeutic strategy to rescue cells from α-synuclein toxicity. The controversial reports on the potential role of sirtuins in the degradation of α-synuclein will be discussed. Connection between sirtuins and proteolytic systems is definitely worth of further studies to increase the knowledge that will allow its proper exploration as new avenue to fight synucleinopathies. Full article

(This article belongs to the Special Issue Exploring the Mechanisms by which α-Synuclein Kills Cells in Parkinson Disease)

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Open AccessReview

Posttranslational Modifications and Clearing of α-Synuclein Aggregates in Yeast

by Blagovesta Popova, Alexandra Kleinknecht and Gerhard H. Braus

Biomolecules 2015, 5(2), 617-634; https://doi.org/10.3390/biom5020617 - 23 Apr 2015

Cited by 34 | Viewed by 9571

Abstract

The budding yeast Saccharomyces cerevisiae represents an established model system to study the molecular mechanisms associated to neurodegenerative disorders. A key-feature of Parkinson’s disease is the formation of Lewy bodies, which are cytoplasmic protein inclusions. Misfolded α-synuclein is one of their main constituents. [...] Read more.

The budding yeast Saccharomyces cerevisiae represents an established model system to study the molecular mechanisms associated to neurodegenerative disorders. A key-feature of Parkinson’s disease is the formation of Lewy bodies, which are cytoplasmic protein inclusions. Misfolded α-synuclein is one of their main constituents. Expression of α-synuclein protein in yeast leads to protein aggregation and cellular toxicity, which is reminiscent to Lewy body containing human cells. The molecular mechanism involved in clearance of α-synuclein aggregates is a central question for elucidating the α-synuclein-related toxicity. Cellular clearance mechanisms include ubiquitin mediated 26S proteasome function as well as lysosome/vacuole associated degradative pathways as autophagy. Various modifications change α-synuclein posttranslationally and alter its inclusion formation, cytotoxicity and the distribution to different clearance pathways. Several of these modification sites are conserved from yeast to human. In this review, we summarize recent findings on the effect of phosphorylation and sumoylation of α-synuclein to the enhanced channeling to either the autophagy or the proteasome degradation pathway in yeast model of Parkinson’s disease. Full article

(This article belongs to the Special Issue Exploring the Mechanisms by which α-Synuclein Kills Cells in Parkinson Disease)

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Open AccessReview

The Interplay between Alpha-Synuclein Clearance and Spreading

by Tomás Lopes da Fonseca, Anna Villar-Piqué and Tiago Fleming Outeiro

Biomolecules 2015, 5(2), 435-471; https://doi.org/10.3390/biom5020435 - 14 Apr 2015

Cited by 82 | Viewed by 13165

Abstract

Parkinson’s Disease (PD) is a complex neurodegenerative disorder classically characterized by movement impairment. Pathologically, the most striking features of PD are the loss of dopaminergic neurons and the presence of intraneuronal protein inclusions primarily composed of alpha-synuclein (α-syn) that are known as Lewy [...] Read more.

Parkinson’s Disease (PD) is a complex neurodegenerative disorder classically characterized by movement impairment. Pathologically, the most striking features of PD are the loss of dopaminergic neurons and the presence of intraneuronal protein inclusions primarily composed of alpha-synuclein (α-syn) that are known as Lewy bodies and Lewy neurites in surviving neurons. Though the mechanisms underlying the progression of PD pathology are unclear, accumulating evidence suggests a prion-like spreading of α-syn pathology. The intracellular homeostasis of α-syn requires the proper degradation of the protein by three mechanisms: chaperone-mediated autophagy, macroautophagy and ubiquitin-proteasome. Impairment of these pathways might drive the system towards an alternative clearance mechanism that could involve its release from the cell. This increased release to the extracellular space could be the basis for α-syn propagation to different brain areas and, ultimately, for the spreading of pathology and disease progression. Here, we review the interplay between α-syn degradation pathways and its intercellular spreading. The understanding of this interplay is indispensable for obtaining a better knowledge of the molecular basis of PD and, consequently, for the design of novel avenues for therapeutic intervention. Full article

(This article belongs to the Special Issue Exploring the Mechanisms by which α-Synuclein Kills Cells in Parkinson Disease)

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Open AccessReview

Seeking a Mechanism for the Toxicity of Oligomeric α-Synuclein

by Hazel L. Roberts and David R. Brown

Biomolecules 2015, 5(2), 282-305; https://doi.org/10.3390/biom5020282 - 25 Mar 2015

Cited by 178 | Viewed by 17666

Abstract

In a number of neurological diseases including Parkinson’s disease (PD), α‑synuclein is aberrantly folded, forming abnormal oligomers, and amyloid fibrils within nerve cells. Strong evidence exists for the toxicity of increased production and aggregation of α-synuclein in vivo. The toxicity of α-synuclein [...] Read more.

In a number of neurological diseases including Parkinson’s disease (PD), α‑synuclein is aberrantly folded, forming abnormal oligomers, and amyloid fibrils within nerve cells. Strong evidence exists for the toxicity of increased production and aggregation of α-synuclein in vivo. The toxicity of α-synuclein is popularly attributed to the formation of “toxic oligomers”: a heterogenous and poorly characterized group of conformers that may share common molecular features. This review presents the available evidence on the properties of α-synuclein oligomers and the potential molecular mechanisms of their cellular disruption. Toxic α-synuclein oligomers may impact cells in a number of ways, including the disruption of membranes, mitochondrial depolarization, cytoskeleton changes, impairment of protein clearance pathways, and enhanced oxidative stress. We also examine the relationship between α-synuclein toxic oligomers and amyloid fibrils, in the light of recent studies that paint a more complex picture of α-synuclein toxicity. Finally, methods of studying and manipulating oligomers within cells are described. Full article

(This article belongs to the Special Issue Exploring the Mechanisms by which α-Synuclein Kills Cells in Parkinson Disease)

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