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

2021 ◽  
pp. 108754
Author(s):  
Ivan A. Kuznetsov ◽  
Andrey V. Kuznetsov
Keyword(s):  
Catalytic Activity ◽  
Lewy Bodies ◽  
Alpha Synuclein

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 The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know

2021 ◽  
Vol 22 (11) ◽  
pp. 5999
Author(s):  
David S. Goldstein
Keyword(s):  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Future Research ◽  
Catecholamine Metabolism ◽  
Secondary Effects ◽  
Drug Induced ◽  
Neuronal Homeostasis ◽  
Mitochondrial Functions ◽  
Environmental Agents ◽  
Spontaneous Oxidation

3,4-Dihydroxyphenylacetaldehyde (DOPAL) is the focus of the catecholaldehyde hypothesis for the pathogenesis of Parkinson’s disease and other Lewy body diseases. The catecholaldehyde is produced via oxidative deamination catalyzed by monoamine oxidase (MAO) acting on cytoplasmic dopamine. DOPAL is autotoxic, in that it can harm the same cells in which it is produced. Normally, DOPAL is detoxified by aldehyde dehydrogenase (ALDH)-mediated conversion to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. Genetic, environmental, or drug-induced manipulations of ALDH that build up DOPAL promote catecholaminergic neurodegeneration. A concept derived from the catecholaldehyde hypothesis imputes deleterious interactions between DOPAL and the protein alpha-synuclein (αS), a major component of Lewy bodies. DOPAL potently oligomerizes αS, and αS oligomers impede vesicular and mitochondrial functions, shifting the fate of cytoplasmic dopamine toward the MAO-catalyzed formation of DOPAL—destabilizing vicious cycles. Direct and indirect effects of DOPAL and of DOPAL-induced misfolded proteins could “freeze” intraneuronal reactions, plasticity of which is required for neuronal homeostasis. The extent to which DOPAL toxicity is mediated by interactions with αS, and vice versa, is poorly understood. Because of numerous secondary effects such as augmented spontaneous oxidation of dopamine by MAO inhibition, there has been insufficient testing of the catecholaldehyde hypothesis in animal models. The clinical pathophysiological significance of genetics, emotional stress, environmental agents, and interactions with numerous proteins relevant to the catecholaldehyde hypothesis are matters for future research. The imposing complexity of intraneuronal catecholamine metabolism seems to require a computational modeling approach to elucidate clinical pathogenetic mechanisms and devise pathophysiology-based, individualized treatments.

scholarly journals Neurons and Glia Interplay in α-Synucleinopathies

2021 ◽  
Vol 22 (9) ◽  
pp. 4994
Author(s):  
Panagiota Mavroeidi ◽  
Maria Xilouri
Keyword(s):  
Glial Cells ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Lewy Neurites ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Glial Function ◽  
Presynaptic Protein

Accumulation of the neuronal presynaptic protein alpha-synuclein within proteinaceous inclusions represents the key histophathological hallmark of a spectrum of neurodegenerative disorders, referred to by the umbrella term a-synucleinopathies. Even though alpha-synuclein is expressed predominantly in neurons, pathological aggregates of the protein are also found in the glial cells of the brain. In Parkinson’s disease and dementia with Lewy bodies, alpha-synuclein accumulates mainly in neurons forming the Lewy bodies and Lewy neurites, whereas in multiple system atrophy, the protein aggregates mostly in the glial cytoplasmic inclusions within oligodendrocytes. In addition, astrogliosis and microgliosis are found in the synucleinopathy brains, whereas both astrocytes and microglia internalize alpha-synuclein and contribute to the spread of pathology. The mechanisms underlying the pathological accumulation of alpha-synuclein in glial cells that under physiological conditions express low to non-detectable levels of the protein are an area of intense research. Undoubtedly, the presence of aggregated alpha-synuclein can disrupt glial function in general and can contribute to neurodegeneration through numerous pathways. Herein, we summarize the current knowledge on the role of alpha-synuclein in both neurons and glia, highlighting the contribution of the neuron-glia connectome in the disease initiation and progression, which may represent potential therapeutic target for a-synucleinopathies.

scholarly journals Multiple system atrophy-associated oligodendroglial protein p25α stimulates formation of novel α-synuclein strain with enhanced neurodegenerative potential

2021 ◽  
Author(s):  
Nelson Ferreira ◽  
Hjalte Gram ◽  
Zachary A. Sorrentino ◽  
Emil Gregersen ◽  
Sissel Ida Schmidt ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Protein Misfolding ◽  
Resonance Energy Transfer ◽  
Lewy Bodies ◽  
Resonance Energy ◽  
Alpha Synuclein ◽  
Striatal Neurons ◽  
End Stage ◽  
Intracellular Aggregates

AbstractPathology consisting of intracellular aggregates of alpha-Synuclein (α-Syn) spread through the nervous system in a variety of neurodegenerative disorders including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. The discovery of structurally distinct α-Syn polymorphs, so-called strains, supports a hypothesis where strain-specific structures are templated into aggregates formed by native α-Syn. These distinct strains are hypothesised to dictate the spreading of pathology in the tissue and the cellular impact of the aggregates, thereby contributing to the variety of clinical phenotypes. Here, we present evidence of a novel α-Syn strain induced by the multiple system atrophy-associated oligodendroglial protein p25α. Using an array of biophysical, biochemical, cellular, and in vivo analyses, we demonstrate that compared to α-Syn alone, a substoichiometric concentration of p25α redirects α-Syn aggregation into a unique α-Syn/p25α strain with a different structure and enhanced in vivo prodegenerative properties. The α-Syn/p25α strain induced larger inclusions in human dopaminergic neurons. In vivo, intramuscular injection of preformed fibrils (PFF) of the α-Syn/p25α strain compared to α-Syn PFF resulted in a shortened life span and a distinct anatomical distribution of inclusion pathology in the brain of a human A53T transgenic (line M83) mouse. Investigation of α-Syn aggregates in brain stem extracts of end-stage mice demonstrated that the more aggressive phenotype of the α-Syn/p25α strain was associated with an increased load of α-Syn aggregates based on a Förster resonance energy transfer immunoassay and a reduced α-Syn aggregate seeding activity based on a protein misfolding cyclic amplification assay. When injected unilaterally into the striata of wild-type mice, the α-Syn/p25α strain resulted in a more-pronounced motoric phenotype than α-Syn PFF and exhibited a “tropism” for nigro-striatal neurons compared to α-Syn PFF. Overall, our data support a hypothesis whereby oligodendroglial p25α is responsible for generating a highly prodegenerative α-Syn strain in multiple system atrophy.

ALPHA SYNUCLEIN IMMUNOREACTIVITY IN DEMENTIA WITH LEWY BODIES

1999 ◽  
Vol 58 (5) ◽  
pp. 553
Author(s):  
E Gómez-Tortosa ◽  
K L Newell ◽  
M C Irizarry ◽  
M Albert ◽  
J H Growdon ◽  
...  
Keyword(s):  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Alpha Synuclein

[P1-243]: ALPHA-SYNUCLEIN SPECIES AS POTENTIAL CSF BIOMARKERS FOR DEMENTIA WITH LEWY BODIES

2017 ◽  
Vol 13 (7S_Part_7) ◽  
pp. P338-P338 ◽  
Author(s):  
Inger van Steenoven ◽  
Nour K. Majbour ◽  
Nishant N. Vaikath ◽  
Henk W. Berendse ◽  
Wiesje M. van der Flier ◽  
...  
Keyword(s):  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Csf Biomarkers

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 (De)stabilization of Alpha-Synuclein Fibrillary Aggregation by Charged and Uncharged Surfactants

2021 ◽  
Vol 22 (22) ◽  
pp. 12509
Author(s):  
Joana Angélica Loureiro ◽  
Stéphanie Andrade ◽  
Lies Goderis ◽  
Ruben Gomez-Gutierrez ◽  
Claudio Soto ◽  
...  
Keyword(s):  
Secondary Structure ◽  
Hydrophobic Interactions ◽  
Neurodegenerative Disorder ◽  
Sodium Dodecyl ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Cetyltrimethylammonium Chloride ◽  
Α Helix ◽  
Β Sheet

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. An important hallmark of PD involves the pathological aggregation of proteins in structures known as Lewy bodies. The major component of these proteinaceous inclusions is alpha (α)-synuclein. In different conditions, α-synuclein can assume conformations rich in either α-helix or β-sheets. The mechanisms of α-synuclein misfolding, aggregation, and fibrillation remain unknown, but it is thought that β-sheet conformation of α-synuclein is responsible for its associated toxic mechanisms. To gain fundamental insights into the process of α-synuclein misfolding and aggregation, the secondary structure of this protein in the presence of charged and non-charged surfactant solutions was characterized. The selected surfactants were (anionic) sodium dodecyl sulphate (SDS), (cationic) cetyltrimethylammonium chloride (CTAC), and (uncharged) octyl β-D-glucopyranoside (OG). The effect of surfactants in α-synuclein misfolding was assessed by ultra-structural analyses, in vitro aggregation assays, and secondary structure analyses. The α-synuclein aggregation in the presence of negatively charged SDS suggests that SDS-monomer complexes stimulate the aggregation process. A reduction in the electrostatic repulsion between N- and C-terminal and in the hydrophobic interactions between the NAC (non-amyloid beta component) region and the C-terminal seems to be important to undergo aggregation. Fourier transform infrared spectroscopy (FTIR) measurements show that β-sheet structures comprise the assembly of the fibrils.

scholarly journals Alpha-synuclein from patient Lewy bodies exhibits distinct pathological activity that can be propagated in vitro

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Nicholas P. Marotta ◽  
Jahan Ara ◽  
Norihito Uemura ◽  
Marshall G. Lougee ◽  
Emily S. Meymand ◽  
...  
Keyword(s):  
Cellular Response ◽  
Amyloid Fibrils ◽  
Cultured Cells ◽  
Biological Activities ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Biological Behavior ◽  
Motor Deficits ◽  
Original Material

AbstractLewy bodies (LBs) are complex, intracellular inclusions that are common pathological features of many neurodegenerative diseases. They consist largely of aggregated forms of the protein alpha-Synuclein (α-Syn), which misfolds to give rise to beta-sheet rich amyloid fibrils. The aggregation of monomers into fibrils occurs readily in vitro and pre-formed fibrils (PFFs) generated from recombinant α-Syn monomers are the basis of many models of LB diseases. These α-Syn PFFs recapitulate many pathological phenotypes in both cultured cells and animal models including the formation of α-Syn rich, insoluble aggregates, neuron loss, and motor deficits. However, it is not clear how closely α-Syn PFFs recapitulate the biological behavior of LB aggregates isolated directly from patients. Direct interrogation of the cellular response to LB-derived α-Syn has thus far been limited. Here we demonstrate that α-Syn aggregates derived from LB disease patients induce pathology characterized by a prevalence of large somatic inclusions that is distinct from the primarily neuritic pathology induced by α-Syn PFFs in our cultured neuron model. Moreover, these LB-derived aggregates can be amplified in vitro using recombinant α-Syn to generate aggregates that maintain the unique, somatic pathological phenotype of the original material. Amplified LB aggregates also showed greater uptake in cultured neurons and greater pathological burden and more rapid pathological spread in injected mouse brains, compared to α-Syn PFFs. Our work indicates that LB-derived α-Syn from diseased brains represents a distinct conformation species with unique biological activities that has not been previously observed in fully recombinant α-Syn aggregates and demonstrate a new strategy for improving upon α-Syn PFF models of synucleinopathies using amplified LBs.

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