scholarly journals Endogenous alpha-synuclein monomers, oligomers and resulting pathology: let’s talk about the lipids in the room

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Bryan A. Killinger ◽  
Ronald Melki ◽  
Patrik Brundin ◽  
Jeffrey H. Kordower
Keyword(s):  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Biological Origin ◽  
Lewy Pathology ◽  
Molecular Weights ◽  
Intrinsically Disordered ◽  
Bona Fide ◽  
Membrane Bound ◽  
Soluble Species ◽  
Alpha Synuclein Aggregation

Abstract Alpha-synuclein is an intrinsically disordered, highly dynamic protein that pathogenically aggregates into inclusion structures called Lewy bodies, in several neurogenerative diseases termed synucleinopathies. Despite its importance for understanding disease, the oligomerization status of alpha-synuclein in healthy cells remains unclear. Alpha-synuclein may exist predominantly as either a monomer or a variety of oligomers of different molecular weights. There is solid evidence to support both theories. Detection of apparent endogenous oligomers are intimately dependent on vesicle and lipid interactions. Here we consider the possibility that apparent endogenous alpha-synuclein oligomers are in fact conformations of membrane-bound alpha-synuclein and not a bona fide stable soluble species. This perspective posits that the formation of any alpha-synuclein oligomers within the cell is likely toxic and interconversion between monomer and oligomer is tightly controlled. This differs from the hypothesis that there is a continuum of endogenous non-toxic oligomers and they convert, through unclear mechanisms, to toxic oligomers. The distinction is important, because it clarifies the biological origin of synucleinopathy. We suggest that a monomer-only, lipid-centric view of endogenous alpha-synuclein aggregation can explain how alpha-synuclein pathology is triggered, and that the interactions between alpha-synuclein and lipids can represent a target for therapeutic intervention. This discussion is well-timed due to recent studies that show lipids are a significant component of Lewy pathology.

scholarly journals Can the lack of fibrillar form of alpha-synuclein in Lewy bodies be explained by its catalytic activity?

2021 ◽  
Author(s):  
Ivan A. Kuznetsov ◽  
Andrey V. Kuznetsov
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Catalytic Activity ◽  
Lewy Bodies ◽  
Sensitivity Study ◽  
Alpha Synuclein ◽  
Therapeutic Interventions ◽  
Model Parameters ◽  
Lewy Pathology ◽  
Membrane Bound

Finding the causative pathophysiological mechanisms for Parkinson's disease (PD) is important for developing therapeutic interventions. Until recently, it was believed that Lewy bodies (LBs), the hallmark of PD, are mostly composed of alpha-synuclein (α-syn) fibrils. Recent results (Shahmoradian et al., Lewy pathology in Parkinson's disease consists of crowded organelles and lipid membranes, Nature Neuroscience 22 (2019) 1099-1109) demonstrated that the fibrillar form of α-syn is lacking from LBs. Here we propose that this surprising observation can be explained by the catalytic activity of the fibrillar form of α-syn. We assumed that α-syn fibrils catalyze the formation of LBs, but do not become part of them. We developed a mathematical model based on this hypothesis. By using the developed model, we investigated the consequences of this hypothesis. In particular, the model suggests that the long incubation time of PD can be explained by a two-step aggregation process that leads to its development: (i) aggregation of monomeric α-syn into α-syn oligomers and fibrils and (ii) clustering of membrane-bound organelles, which may cause disruption of axonal trafficking and lead to neuron starvation and death. The model shows that decreasing the rate of destruction of α-syn aggregates in somatic lysosomes accelerates the formation of LBs. Another consequence of the model is the prediction that removing α-syn aggregates from the brain after the aggregation of membrane-bound organelles into LBs has started may not stop the progression of PD because LB formation is an autocatalytic process; hence, the formation of LBs will be catalyzed by aggregates of membrane-bound organelles even in the absence of α-syn aggregates. The performed sensitivity study made it possible to establish the hierarchy of model parameters with respect to their effect on the formation of vesicle aggregates in the soma.

Are lysosomes potential therapeutic targets for Parkinson’s disease?

2021 ◽  
Vol 20 ◽  
Author(s):  
A. Petese ◽  
V. Cesaroni ◽  
S. Cerri ◽  
F. Blandini
Keyword(s):  
Neurodegenerative Disorder ◽  
Association Studies ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Genome Wide Association Studies ◽  
Lysosomal Dysfunction ◽  
Genome Wide ◽  
Nigrostriatal Neurons ◽  
Disease Modifying Treatment ◽  
Alpha Synuclein Aggregation

Background: Parkinson´s disease (PD) is the second most common neurodegenerative disorder, affecting 2-3% of the population over 65 years old. In addition to progressive degeneration of nigrostriatal neurons, the histopathological feature of PD is the accumulation of misfolded α-synuclein protein in abnormal cytoplasmatic inclusions, known as Lewy bodies (LBs). Recently, genome-wide association studies (GWAS) have indicated a clear association of variants within several lysosomal genes with risk for PD. Newly evolving data have been shedding light on the relationship between lysosomal dysfunction and alpha-synuclein aggregation. Defects in lysosomal enzymes could lead to the insufficient clearance of neurotoxic protein materials, possibly leading to selective degeneration of dopaminergic neurons. Specific modulation of lysosomal pathways and their components could be considered a novel opportunity for therapeutic intervention for PD. Aim: The purpose of this review is to illustrate lysosomal biology and describe the role of lysosomal dysfunction in PD pathogenesis. Finally, the most promising novel therapeutic approaches designed to modulate lysosomal activity, as a potential disease-modifying treatment for PD will be highlighted.

scholarly journals Blood Plasma of Patients with Parkinson’s Disease Increases Alpha-Synuclein Aggregation and Neurotoxicity

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Peng Wang ◽  
Xin Li ◽  
Xuran Li ◽  
Weiwei Yang ◽  
Shun Yu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Alternative Pathway ◽  
Lewy Bodies ◽  
Normal Subjects ◽  
Alpha Synuclein ◽  
Phosphatase 2A ◽  
Alpha Synuclein Aggregation ◽  
The Brain ◽  
Neighboring Neuron

A pathological hallmark of Parkinson’s disease (PD) is formation of Lewy bodies in neurons of the brain. This has been attributed to the spread of α-synuclein (α-syn) aggregates, which involves release of α-syn from a neuron and its reuptake by a neighboring neuron. We found that treatment with plasma from PD patients induced more α-syn phosphorylation and oligomerization than plasma from normal subjects (NS). Compared with NS plasma, PD plasma added to primary neuron cultures caused more cell death in the presence of extracellular α-syn. This was supported by the observations that phosphorylated α-syn oligomers entered neurons, rapidly increased accumulated thioflavin S-positive inclusions, and induced a series of metabolic changes that included activation of polo-like kinase 2, inhibition of glucocerebrosidase and protein phosphatase 2A, and reduction of ceramide levels, all of which have been shown to promote α-syn phosphorylation and aggregation. We also analyzed neurotoxicity of α-syn oligomers relative to plasma from different patients. Neurotoxicity was not related to age or gender of the patients. However, neurotoxicity was positively correlated with H&Y staging score. The modification in the plasma may promote spreading of α-syn aggregates via an alternative pathway and accelerate progression of PD.

scholarly journals Polo-like kinase 2 inhibition reduces serine-129 phosphorylation of physiological nuclear alpha-synuclein but not of the aggregated alpha-synuclein

2021 ◽  
Author(s):  
Sara Elfarrash ◽  
Nanna Møller Jensen ◽  
Nelson Ferreira ◽  
Sissel Ida Schmidt ◽  
Emil Gregersen ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Signal To Noise Ratio ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Sample Collection ◽  
Lewy Pathology ◽  
Organotypic Brain Slice ◽  
Short Time

Accumulation of aggregated alpha-synuclein (α-syn) is believed to play a pivotal role in the pathophysiology of Parkinson’s disease (PD) and other synucleinopathies. α-Syn is a key constituent protein of  Lewy pathology, and α-syn phosphorylated at serine-129 (pS129) constitutes more than 90% of α-syn in Lewy bodies and hence, it is used extensively as a pathological marker for the aggregated form of α-syn. However, the exact role of pS129 remains controversial as well as the kinase(s) responsible for the phosphorylation. In this study, we investigated the effect of Polo-like kinase 2 (PLK2) inhibition on formation of pS129 using ex-vivo organotypic brain slice model of synucleinopathy. Our data demonstrated that PLK2 inhibition has no effect on α-syn aggregation, pS129 or inter-neuronal spreading of the aggregated α-syn seen in the organotypic slices. Instead, PLK2 inhibition reduced the soluble nuclear pS129 level confined in the nuclei. The same finding was replicated in an in-vivo mouse models of templated α-syn aggregation and human dopaminergic neurons, suggesting that PLK2 is more likely to be involved in S129 phosphorylation of soluble non-pathology related fraction of α-syn. We also demonstrated that reduction of nuclear pS129 but not the aggregates specific pS129 following PLK2 inhibition for a short time before sample collection improves the signal to noise ratio when quantifying pS129 aggregate pathology.

scholarly journals Living in Promiscuity: The Multiple Partners of Alpha-Synuclein at the Synapse in Physiology and Pathology

2019 ◽  
Vol 20 (1) ◽  
pp. 141 ◽  
Author(s):  
Francesca Longhena ◽  
Gaia Faustini ◽  
Maria Grazia Spillantini ◽  
Arianna Bellucci
Keyword(s):  
Lipid Membranes ◽  
Intrinsically Disordered Proteins ◽  
Lipid Membrane ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Disordered Proteins ◽  
Monoamine Transporters ◽  
Post Translational Modification ◽  
Intrinsically Disordered ◽  
Multiple Partners

Alpha-synuclein (α-syn) is a small protein that, in neurons, localizes predominantly to presynaptic terminals. Due to elevated conformational plasticity, which can be affected by environmental factors, in addition to undergoing disorder-to-order transition upon interaction with different interactants, α-syn is counted among the intrinsically disordered proteins (IDPs) family. As with many other IDPs, α-syn is considered a hub protein. This function is particularly relevant at synaptic sites, where α-syn is abundant and interacts with many partners, such as monoamine transporters, cytoskeletal components, lipid membranes, chaperones and synaptic vesicles (SV)-associated proteins. These protein–protein and protein–lipid membrane interactions are crucial for synaptic functional homeostasis, and alterations in α-syn can cause disruption of this complex network, and thus a failure of the synaptic machinery. Alterations of the synaptic environment or post-translational modification of α-syn can induce its misfolding, resulting in the formation of oligomers or fibrillary aggregates. These α-syn species are thought to play a pathological role in neurodegenerative disorders with α-syn deposits such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), which are referred to as synucleinopathies. Here, we aim at revising the complex and promiscuous role of α-syn at synaptic terminals in order to decipher whether α-syn molecular interactants may influence its conformational state, contributing to its aggregation, or whether they are just affected by it.

scholarly journals Srpk3 Decrease Associated with Alpha-Synuclein Increase in Muscles of MPTP-Induced Parkinson’s Disease Mice

2021 ◽  
Vol 22 (17) ◽  
pp. 9375
Author(s):  
Min Hyung Seo ◽  
Sujung Yeo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
C2c12 Cell ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
C2c12 Cells ◽  
Control Group ◽  
Lewy Neurites ◽  
Lewy Pathology ◽  
Interfering Rna

Parkinson’s disease (PD) is characterized by a loss of dopaminergic cells in the substantia nigra, and its histopathological features include the presence of fibrillar aggregates of α-synuclein (α-syn), which are called Lewy bodies and Lewy neurites. Lewy pathology has been identified not only in the brain but also in various tissues, including muscles. This study aimed to investigate the link between serine/arginine-rich protein specific kinase 3 (srpk3) and α-syn in muscles in PD. We conducted experiments on the quadriceps femoris of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model and the C2C12 cell line after treatment with 1-methyl-4-phenylpyridinium (MPP+) and srpk3 short interfering RNA (siRNA). Compared to the control group, the MPTP group showed significantly reduced expression of srpk3, but increased expression of α-syn. In MPP+-treated C2C12 cells, srpk3 expression gradually decreased and α-syn expression increased with the increasing MPP+ concentration. Moreover, experiments in C2C12 cells using srpk3 siRNA showed increased expressions of α-syn and phosphorylated α-syn. Our results showed that srpk3 expression could be altered by MPTP intoxication in muscles, and this change may be related to changes in α-syn expression. Furthermore, this study could contribute to advancement of research on the mechanism by which srpk3 plays a role in PD.

scholarly journals Toward a Disease-Modifying Therapy of Alpha-Synucleinopathies: New Molecules and New Approaches Came into the Limelight

Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7351
Author(s):  
Matthew Upcott ◽  
Kirill D. Chaprov ◽  
Vladimir L. Buchman
Keyword(s):  
Clinical Trials ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Therapeutic Window ◽  
Disease Modifying Therapy ◽  
Stage Of Development ◽  
Phase Ii Clinical Trials ◽  
Modifying Effect ◽  
Disease Modifying ◽  
Alpha Synuclein Aggregation

The accumulation of the various products of alpha-synuclein aggregation has been associated with the etiology and pathogenesis of several neurodegenerative conditions, including both familial and sporadic forms of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). It is now well established that the aggregation and spread of alpha-synuclein aggregation pathology activate numerous pathogenic mechanisms that contribute to neurodegeneration and, ultimately, to disease progression. Therefore, the development of a safe and effective disease-modifying therapy that limits or prevents the accumulation of the toxic intermediate products of alpha-synuclein aggregation and the spread of alpha-synuclein aggregation pathology could provide significant positive clinical outcomes in PD/DLB cohorts. It has been suggested that this goal can be achieved by reducing the intracellular and/or extracellular levels of monomeric and already aggregated alpha-synuclein. The principal aim of this review is to critically evaluate the potential of therapeutic strategies that target the post-transcriptional steps of alpha-synuclein production and immunotherapy-based approaches to alpha-synuclein degradation in PD/DLB patients. Strategies aimed at the downregulation of alpha-synuclein production are at an early preclinical stage of drug development and, although they have shown promise in animal models of alpha-synuclein aggregation, many limitations need to be resolved before in-human clinical trials can be seriously considered. In contrast, many strategies aimed at the degradation of alpha-synuclein using immunotherapeutic approaches are at a more advanced stage of development, with some in-human Phase II clinical trials currently in progress. Translational barriers for both strategies include the limitations of alpha-synuclein aggregation models, poor understanding of the therapeutic window for the alpha-synuclein knockdown, and variability in alpha-synuclein pathology across patient cohorts. Overcoming such barriers should be the main focus of further studies. However, it is already clear that these strategies do have the potential to achieve a disease-modifying effect in PD and DLB.

scholarly journals Poly (ADP-ribose) Interacts With Phosphorylated α-Synuclein in Post Mortem PD Samples

2021 ◽  
Vol 13 ◽  
Author(s):  
Laura N. Puentes ◽  
Zsofia Lengyel-Zhand ◽  
Ji Youn Lee ◽  
Chia-Ju Hsieh ◽  
Mark E. Schneider ◽  
...  
Keyword(s):  
Lewy Bodies ◽  
Intrinsically Disordered Protein ◽  
Alpha Synuclein ◽  
Site Directed Mutagenesis ◽  
Post Mortem ◽  
Lewy Neurites ◽  
Intrinsically Disordered ◽  
Transgenic Murine Model ◽  
Transgenic Murine Models ◽  
Parp 1

Poly (ADP-ribose) (PAR) is a negatively charged polymer that is biosynthesized by Poly (ADP-ribose) Polymerase-1 (PARP-1) and regulates various cellular processes. Alpha-synuclein (αSyn) is an intrinsically disordered protein (IDP) that has been directly implicated with driving the onset and progression of Parkinson’s disease (PD). The mechanisms by which α-synuclein (αSyn) elicits its neurotoxic effects remain unclear, though it is well established that the main components of Lewy bodies (LBs) and Lewy neurites (LNs) in PD patients are aggregated hyperphosphorylated (S129) forms of αSyn (pαSyn). In the present study, we used immunofluorescence-based assays to explore if PARP-1 enzymatic product (PAR) promotes the aberrant cytoplasmic accumulation of pαSyn. We also performed quantitative measurements using in situ proximity ligation assays (PLA) on a transgenic murine model of α-synucleinopathy (M83-SNCA∗A53T) and post mortem PD/PDD patient samples to characterize PAR–pαSyn interactions. Additionally, we used bioinformatic approaches and site-directed mutagenesis to identify PAR-binding regions on αSyn. In summary, our studies show that PAR–pαSyn interactions are predominantly observed in PD-relevant transgenic murine models of αSyn pathology and post mortem PD/PDD patient samples. Moreover, we confirm that the interactions between PAR and αSyn involve electrostatic forces between negatively charged PAR and lysine residues on the N-terminal region of αSyn.

Parkinson’s Disease: Alpha Synuclein, Heme Oxygenase and Biotherapeutic Countermeasures

2018 ◽  
Vol 24 (20) ◽  
pp. 2317-2321 ◽  
Author(s):  
David D. Haines ◽  
Maxim V. Trushin ◽  
Stephen Rose ◽  
Iloki Assanga Simon Bernard ◽  
Fadia F. Mahmoud
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Heme Oxygenase ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Human Relationships ◽  
Midbrain Neurons ◽  
Glycation End Products ◽  
Botulinum Neurotoxins ◽  
Alpha Synuclein Aggregation

Neurodegenerative disorders have been and remain persistent sources of enormous suffering throughout human history. The tragedy of their impact on human relationships, physical vitality, and fundamental dignity cannot be understated. Parkinson’s disease (PD), one of the most common of these terrible illnesses, has a global incidence of approximately two-to-four percent of the human population, along with devastating social and economic impact. The present review analyzes aspects of PD pathophysiology that offer particularly attractive strategies for the development of improved prevention and therapy. The occurrence, symptoms, pathogenesis, and etiology of PD are considered, with focus on how the Alpha synuclein protein, which normally regulates neurotransmitter release, is aggregated by oxidative stressors into toxic inclusions, prominently including Lewy bodies and insoluble fibrils that disrupt the organization of brain areas responsible for motor control. The contribution to a progressively prooxidant tissue environment resulting from interaction between advanced glycation end products (AGEs) and their cognate receptors (RAGEs) is examined here as a significant driver of PD. This review also explores strategies currently being developed by a U.S.-Russian team that may reduce the risk and severity of PD by use of recombinant atoxic derivatives (ad) of botulinum neurotoxins (BoNT/A ad), that traffic inducers of the cytoprotective enzyme heme oxygenase to selected midbrain neurons, at which Alpha synuclein aggregation occurs. Considered together, the topic material presented here provides both researchers and clinicians with a short but concise overview of the current understanding of PD pathology and approaches to biotherapeutic (precision) countermeasures to its onset and progression.

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