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.

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 Synucleinopathy-associated pathogenesis in Parkinson’s disease and the potential for brain-derived neurotrophic factor

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Kathryn M. Miller ◽  
Natosha M. Mercado ◽  
Caryl E. Sortwell
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurotrophic Factor ◽  
Lewy Bodies ◽  
Brain Derived Neurotrophic Factor ◽  
Alpha Synuclein ◽  
Comprehensive Overview ◽  
Lewy Pathology ◽  
Disease Modifying

AbstractThe lack of disease-modifying treatments for Parkinson’s disease (PD) is in part due to an incomplete understanding of the disease’s etiology. Alpha-synuclein (α-syn) has become a point of focus in PD due to its connection to both familial and idiopathic cases—specifically its localization to Lewy bodies (LBs), a pathological hallmark of PD. Within this review, we will present a comprehensive overview of the data linking synuclein-associated Lewy pathology with intracellular dysfunction. We first present the alterations in neuronal proteins and transcriptome associated with LBs in postmortem human PD tissue. We next compare these findings to those associated with LB-like inclusions initiated by in vitro exposure to α-syn preformed fibrils (PFFs) and highlight the profound and relatively unique reduction of brain-derived neurotrophic factor (BDNF) in this model. Finally, we discuss the multitude of ways in which BDNF offers the potential to exert disease-modifying effects on the basal ganglia. What remains unknown is the potential for BDNF to mitigate inclusion-associated dysfunction within the context of synucleinopathy. Collectively, this review reiterates the merit of using the PFF model as a tool to understand the physiological changes associated with LBs, while highlighting the neuroprotective potential of harnessing endogenous BDNF.

scholarly journals Subcellular orchestration of alpha-synuclein variants in Parkinson’s disease brains revealed by 3D multicolor STED microscopy

2018 ◽  
Author(s):  
Tim E. Moors ◽  
Christina A. Maat ◽  
Daniel Niedieker ◽  
Daniel Mona ◽  
Dennis Petersen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Distribution Patterns ◽  
Alpha Synuclein ◽  
Label Free ◽  
Post Translational Modifications ◽  
Sted Microscopy ◽  
C Terminus

AbstractPost-translational modifications of alpha-synuclein (aSyn), particularly phosphorylation at Serine 129 (Ser129-p) and truncation of its C-terminus (CTT), have been implicated in Parkinson’s disease (PD) pathology. To gain more insight in the relevance of Ser129-p and CTT aSyn under physiological and pathological conditions, we investigated their subcellular distribution patterns in normal aged and PD brains using highly-selective antibodies in combination with 3D multicolor STED microscopy. We show that CTT aSyn localizes in mitochondria in PD patients and controls, whereas the organization of Ser129-p in a cytoplasmic network is strongly associated with pathology. Nigral Lewy bodies show an onion skin-like architecture, with a structured framework of Ser129-p aSyn and neurofilaments encapsulating CTT aSyn in their core, which displayed high content of proteins and lipids by label-free CARS microscopy. The subcellular phenotypes of antibody-labeled pathology identified in this study provide evidence for a crucial role of Ser129-p aSyn in Lewy body formation.

scholarly journals Cryo-EM structure of alpha-synuclein fibrils

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Ricardo Guerrero-Ferreira ◽  
Nicholas MI Taylor ◽  
Daniel Mona ◽  
Philippe Ringler ◽  
Matthias E Lauer ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Diagnosis And Treatment ◽  
Lewy Neurites ◽  
Cryo Electron Microscopy ◽  
High Concentrations ◽  
Hydrophobic Cleft

Parkinson’s disease is a progressive neuropathological disorder that belongs to the class of synucleinopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils (residues 1–121), determined by cryo-electron microscopy at a resolution of 3.4 Å. Two protofilaments form a polar fibril composed of staggered β-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50–57, containing three of the mutation sites associated with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft at one end of the fibril may have implications for fibril elongation, and invites for the design of molecules for diagnosis and treatment of synucleinopathies.

What Is Known about the Cause

2013 ◽  
Author(s):  
J. Eric Ahlskog
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Medical Center ◽  
Single Gene ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Early Years ◽  
Gene Coding ◽  
Sporadic Parkinson’S Disease ◽  
High Concentrations

Most of the research into the cause of Lewy disorders has focused on Parkinson’s disease, since that is the best defined of these conditions and, therefore, the most straightforward to study. Dementia with Lewy bodies (DLB) is more difficult to diagnose with certainty, especially in the early years of the disease. What we collectively learn about Parkinson’s disease will likely be very relevant to our understanding of DLB. Multiple investigations have linked Parkinson’s disease to both environmental exposures and genetic factors. However, these associations have all been modest, and none of them accounts for more than a few percent of the contribution to the cause of sporadic Parkinson’s disease (i.e., the attributable risks are low). These investigations are ongoing and hopefully will soon provide a more complete understanding of the cause(s). Perhaps the most important clue to all Lewy conditions is located in the brain: the Lewy body itself. A recent sophisticated analysis of Lewy bodies revealed approximately 300 different component proteins. However, we already knew that Lewy bodies contain high concentrations of a normal protein called alpha synuclein. In fact, Lewy bodies are conventionally identified under the microscope with antibody stains that specifically bind to alpha synuclein. Could this be the crucial protein among the nearly 300? While the alpha synuclein story is focused on Parkinson’s disease, it may be just as relevant to DLB, as we shall see. The story starts with a large Italian-American family with Parkinson’s disease, studied by Dr. Lawrence Golbe and colleagues at the Robert Wood Johnson Medical Center in New Brunswick, New Jersey. In this rare family, many members of multiple generations had been affected by Parkinson’s disease (with Lewy bodies), consistent with a single gene passed on with dominant inheritance. It took a number of years to identify that abnormal gene, which ultimately was proven to be the gene coding for alpha synuclein. It was quickly discovered that this genetic error is not present in usual cases of Parkinson’s disease.

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 Cytotoxicity and Mitochondrial Dysregulation Caused by α-Synuclein in Dictyostelium discoideum

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2289 ◽  
Author(s):  
Sanjanie Fernando ◽  
Claire Y. Allan ◽  
Katelyn Mroczek ◽  
Xavier Pearce ◽  
Oana Sanislav ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dictyostelium Discoideum ◽  
Mitochondrial Function ◽  
Molecular Mechanisms ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Cell Cortex ◽  
Mutant Proteins ◽  
C Terminus

Alpha synuclein has been linked to both sporadic and familial forms of Parkinson’s disease (PD) and is the most abundant protein in Lewy bodies a hallmark of Parkinson’s disease. The function of this protein and the molecular mechanisms underlying its toxicity are still unclear, but many studies have suggested that the mechanism of α-synuclein toxicity involves alterations to mitochondrial function. Here we expressed human α-synuclein and two PD-causing α-synuclein mutant proteins (with a point mutation, A53T, and a C-terminal 20 amino acid truncation) in the eukaryotic model Dictyostelium discoideum. Mitochondrial disease has been well studied in D. discoideum and, unlike in mammals, mitochondrial dysfunction results in a clear set of defective phenotypes. These defective phenotypes are caused by the chronic hyperactivation of the cellular energy sensor, AMP-activated protein kinase (AMPK). Expression of α-synuclein wild type and mutant forms was toxic to the cells and mitochondrial function was dysregulated. Some but not all of the defective phenotypes could be rescued by down regulation of AMPK revealing both AMPK-dependent and -independent mechanisms. Importantly, we also show that the C-terminus of α-synuclein is required and sufficient for the localisation of the protein to the cell cortex in D. discoideum.

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 Variants in the Niemann-Pick type C gene NPC1 are not associated with Parkinson’s disease

2020 ◽  
Author(s):  
Bouchra Ouled Amar Bencheikh ◽  
Konstantin Senkevich ◽  
Uladzislau Rudakou ◽  
Eric Yu ◽  
Kheireddin Mufti ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rare Variants ◽  
Transmembrane Protein ◽  
Alpha Synuclein ◽  
Common Variants ◽  
Optimal Sequence ◽  
Lewy Pathology ◽  
Type C ◽  
Niemann Pick

AbstractBiallelic variants in NPC1, a lysosomal gene coding for a transmembrane protein involved in cholesterol trafficking, may cause Niemann-Pick disease type C (NPC). A few cases of NPC1 mutation carriers have been reported with a Parkinson’s disease (PD) presentation. In addition, pathological studies demonstrated phosphorylated alpha-synuclein and Lewy pathology in brains of NPC patients. Therefore, we aimed to examine whether NPC1 genetic variants may be associated with PD. Full sequencing of NPC1 was performed in 2,657 PD patients and 3,647 controls from three cohorts, using targeted sequencing with molecular inversion probes. A total of 9 common variants and 126 rare variants were identified across the three cohorts. To examine association with PD, regression models adjusted for age, sex and origin were performed for common variants, and optimal sequence Kernel association test (SKAT-O) was performed for rare variants. After correction for multiple comparisons, common and rare NPC1 variants were not associated with PD. Our results do not support a link between heterozygous variants in NPC1 and PD.

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