Widespread occurrence of alpha-synuclein/NACP-immunoreactive neuronal inclusions in juvenileand adult-onset Hallervorden-Spatz diseasewith Lewy bodies

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.

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Neurons and Glia Interplay in α-Synucleinopathies

International Journal of Molecular Sciences ◽

10.3390/ijms22094994 ◽

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.

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

Acta Neuropathologica ◽

10.1007/s00401-021-02316-0 ◽

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.

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ALPHA SYNUCLEIN IMMUNOREACTIVITY IN DEMENTIA WITH LEWY BODIES

Journal of Neuropathology & Experimental Neurology ◽

10.1097/00005072-199905000-00188 ◽

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

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

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.06.063 ◽

2017 ◽

Vol 13 (7S_Part_7) ◽

pp. P338-P338 ◽

Cited By ~ 2

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

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Are lysosomes potential therapeutic targets for Parkinson’s disease?

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527320666210809123630 ◽

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms222212509 ◽

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.

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

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01288-2 ◽

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

10.1101/470476 ◽

2018 ◽

Cited By ~ 7

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.

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Cryo-EM structure of alpha-synuclein fibrils

eLife ◽

10.7554/elife.36402 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 188

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.

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