Immunisation with UB-312 in the Thy1SNCA mouse prevents motor performance deficits and oligomeric α-synuclein accumulation in the brain and gut

AbstractAlpha synuclein has a key role in the pathogenesis of Parkinson’s disease (PD), Dementia with Lewy Bodies (LBD) and Multiple System Atrophy (MSA). Immunotherapies aiming at neutralising toxic αSyn species are being investigated in the clinic as potential disease modifying therapies for PD and other synucleinopathies. In this study, the effects of active immunisation against αSyn with the UB-312 vaccine were investigated in the Thy1SNCA/15 mouse model of PD. Young transgenic and wild-type mice received an immunisation regimen over a period of 6 weeks, then observed for an additional 9 weeks. Behavioural assessment was conducted before immunisation and at 15 weeks after the first dose. UB-312 immunisation prevented the development of motor impairment in the wire test and challenging beam test, which was associated with reduced levels of αSyn oligomers in the cerebral cortex, hippocampus and striatum of Thy1SNCA/15 mice. UB-312 immunotherapy resulted in a significant reduction of theαSyn load in the colon, accompanied by a reduction in enteric glial cell reactivity in the colonic ganglia. Our results demonstrate that immunisation with UB-312 prevents functional deficits and both central and peripheral pathology in Thy1SNCA/15 mice.

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

Parkinson s Disease ◽

10.1155/2016/7596482 ◽

2016 ◽

Vol 2016 ◽

pp. 1-14 ◽

Cited By ~ 2

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.

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Slow Progressive Accumulation of Oligodendroglial Alpha-Synuclein (α-Syn) Pathology in Synthetic α-Syn Fibril-Induced Mouse Models of Synucleinopathy

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlz070 ◽

2019 ◽

Vol 78 (10) ◽

pp. 877-890 ◽

Cited By ~ 10

Author(s):

Norihito Uemura ◽

Maiko T Uemura ◽

Angela Lo ◽

Fares Bassil ◽

Bin Zhang ◽

...

Keyword(s):

White Matter ◽

Multiple System Atrophy ◽

Parkinson Disease ◽

Mouse Models ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Wild Type ◽

Time Points ◽

Progressive Accumulation

Abstract Synucleinopathies are composed of Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Alpha-synuclein (α-Syn) forms aggregates mainly in neurons in PD and DLB, while oligodendroglial α-Syn aggregates are characteristic of MSA. Recent studies have demonstrated that injections of synthetic α-Syn preformed fibrils (PFFs) into the brains of wild-type (WT) animals induce intraneuronal α-Syn aggregates and the subsequent interneuronal transmission of α-Syn aggregates. However, injections of α-Syn PFFs or even brain lysates of patients with MSA have not been reported to induce oligodendroglial α-Syn aggregates, raising questions about the pathogenesis of oligodendroglial α-Syn aggregates in MSA. Here, we report that WT mice injected with mouse α-Syn (m-α-Syn) PFFs develop neuronal α-Syn pathology after short postinjection (PI) intervals on the scale of weeks, while oligodendroglial α-Syn pathology emerges after longer PI intervals of several months. Abundant oligodendroglial α-Syn pathology in white matter at later time points is reminiscent of MSA. Furthermore, comparison between young and aged mice injected with m-α-Syn PFFs revealed that PI intervals rather than aging correlate with oligodendroglial α-Syn aggregation. These results provide novel insights into the pathological mechanisms of oligodendroglial α-Syn aggregation in MSA.

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Abstract 454: Mechanism of Alpha-Synuclein Inhibition of Platelet Granule Exocytosis

Circulation ◽

10.1161/circ.116.suppl_16.ii_76-a ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Kalyan Srivastava ◽

Michael Lee ◽

Craig Morrell

Keyword(s):

Atpase Activity ◽

Ex Vivo ◽

Thrombus Formation ◽

Alpha Synuclein ◽

Negative Regulator ◽

Wild Type ◽

In Vivo Models ◽

Granule Exocytosis ◽

The Brain

Alpha-synuclein is only expressed in the brain and platelets. The normal function of alpha-synuclein in the brain is not known, but studies indicate it is an inhibitor of exocytosis in platelets. Platelet granule exocytosis is an important step in stable thrombus formation and its regulatory mechanisms are poorly defined. We therefore sought to determine the mechanism of alpha-synuclein inhibition of exocytosis. Using platelets from alpha-synuclein knockout (syn−/−) mice we first confirmed that syn−/− mice have increased alpha-granule release in response to agonist stimulation as compared to wild-type (WT) control mice. Using a mesenteric intravital microscopy model, we have also found that syn−/− mice have shortened time to thrombus formation as compared to wild-type control mice. The granule exocytosis and thrombosis phenotypic changes are restored to normal in syn null mice made transgenic to express human alpha-synuclein, clearly demonstrating that alpha-synuclein is an inhibitor of exocytosis in platelets. We have also determined the mechanism by which alpha-synuclein inhibits platelet granule exocytosis. Alpha-synuclein interacts with the exocytosis associated molecule Rab3, a modulator of the ATPase molecule N-ethylmaleimide Sensitive Factor (NSF). NSF activity is necessary for exocytosis and is increased by Rab3 interactions. Using platelet lysates, addition of an excess of recombinant alpha-synuclein inhibits NSF and Rab3 co-immunoprecipitation. Furthermore, syn−/− mouse platelets have increased Rab3 immunoprecipitation with NSF as compared to WT controls, that is restored to normal in synuclein Tg mice. Using recombinant tagged alpha-synuclein, NSF, and Rab3 in pull down assays we have confirmed that alpha-synuclein inhibits NSF-Rab3 interactions, and furthermore, decreases NSF ATPase activity. In summary, we now demonstrate using in vitro, ex vivo, and in vivo models that alpha-synuclein is a negative regulator of platelet granule exocytosis by inhibiting NSF-Rab3 association and thus NSF ATPase activity.

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Intrastriatal injection of preformed alpha-synuclein fibrils alters central and peripheral immune cell profiles in non-transgenic mice

Journal of Neuroinflammation ◽

10.1186/s12974-019-1636-8 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 9

Author(s):

Rachael H. Earls ◽

Kelly B. Menees ◽

Jaegwon Chung ◽

James Barber ◽

Claire-Anne Gutekunst ◽

...

Keyword(s):

Immune Responses ◽

Immune Cell ◽

Lewy Bodies ◽

Brain Regions ◽

Alpha Synuclein ◽

Molecular Pattern ◽

Immune Phenotypes ◽

Spleen And Lymph Nodes ◽

The Brain ◽

Intrastriatal Injection

AbstractParkinson’s disease (PD) is characterized by the accumulation of alpha-synuclein (α-syn) inclusions, the major component of Lewy bodies. Extracellular α-syn aggregates act as a damage-associated molecular pattern (DAMP) and the presence of autoantibodies against α-syn species in the cerebrospinal fluid and the serum of PD patients implicate the involvement of innate and adaptive immune responses. In non-transgenic (Tg) mice, intrastriatal injection of preformed fibril (PFF) α-syn results in widespread pathologic α-syn inclusions in the CNS. While the PFF model has been broadly utilized to study the mechanistic relationship between α-syn transmission and other neuropathological phenotypes, the immune phenotypes in this model are not clearly demonstrated. This study aimed to characterize the immune phenotypes during pathologic α-syn propagation by utilizing PFF α-syn–injected non-tg mice. Here, we showed that pathologic α-syn inclusions are prevalent in various brain regions and the gut at 5 months post injection (p.i.), preceding the degeneration of dopaminergic neurons in substantia nigra (SN). We discovered a distinct inflammatory response involving both activation of microglia and astrocytes and infiltration of B, CD4+ T, CD8+ T, and natural killer cells in the brain at 5 months p.i. Moreover, PFF α-syn–injected mice display significant alterations in the frequency and number of leukocyte subsets in the spleen and lymph nodes with minimum alterations in the blood. Our data provide primary evidence that intracerebral-initiated synucleinopathies in non-tg mice alter immune cell profiles both in the CNS and peripheral lymphoid organs. Furthermore, our data provides support for utilizing this mouse model to assess the mechanistic connection between immune responses and synuclein pathology.

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The Gut–Brain Axis and Its Relation to Parkinson’s Disease: A Review

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.782082 ◽

2022 ◽

Vol 13 ◽

Author(s):

Emily M. Klann ◽

Upuli Dissanayake ◽

Anjela Gurrala ◽

Matthew Farrer ◽

Aparna Wagle Shukla ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Current Knowledge ◽

Lewy Bodies ◽

Disease Diagnosis ◽

Alpha Synuclein ◽

Motor Symptoms ◽

Abnormal Gait ◽

Non Motor Symptoms ◽

The Brain

Parkinson’s disease is a chronic neurodegenerative disease characterized by the accumulation of misfolded alpha-synuclein protein (Lewy bodies) in dopaminergic neurons of the substantia nigra and other related circuitry, which contribute to the development of both motor (bradykinesia, tremors, stiffness, abnormal gait) and non-motor symptoms (gastrointestinal issues, urinogenital complications, olfaction dysfunction, cognitive impairment). Despite tremendous progress in the field, the exact pathways and mechanisms responsible for the initiation and progression of this disease remain unclear. However, recent research suggests a potential relationship between the commensal gut bacteria and the brain capable of influencing neurodevelopment, brain function and health. This bidirectional communication is often referred to as the microbiome–gut–brain axis. Accumulating evidence suggests that the onset of non-motor symptoms, such as gastrointestinal manifestations, often precede the onset of motor symptoms and disease diagnosis, lending support to the potential role that the microbiome–gut–brain axis might play in the underlying pathological mechanisms of Parkinson’s disease. This review will provide an overview of and critically discuss the current knowledge of the relationship between the gut microbiota and Parkinson’s disease. We will discuss the role of α-synuclein in non-motor disease pathology, proposed pathways constituting the connection between the gut microbiome and the brain, existing evidence related to pre- and probiotic interventions. Finally, we will highlight the potential opportunity for the development of novel preventative measures and therapeutic options that could target the microbiome–gut–brain axis in the context of Parkinson’s disease.

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Alpha-Synuclein in the Regulation of Brain Endothelial and Perivascular Cells: Gaps and Future Perspectives

Frontiers in Immunology ◽

10.3389/fimmu.2021.611761 ◽

2021 ◽

Vol 12 ◽

Author(s):

Tizibt Ashine Bogale ◽

Gaia Faustini ◽

Francesca Longhena ◽

Stefania Mitola ◽

Marina Pizzi ◽

...

Keyword(s):

Lewy Bodies ◽

Lewy Body Dementia ◽

Alpha Synuclein ◽

Future Perspectives ◽

Lewy Neurites ◽

Cytoskeleton Organization ◽

Pathological Conditions ◽

Neurological Conditions ◽

Er Homeostasis ◽

The Brain

Misfolded proteins, inflammation, and vascular alterations are common pathological hallmarks of neurodegenerative diseases. Alpha-synuclein is a small synaptic protein that was identified as a major component of Lewy bodies and Lewy neurites in the brain of patients affected by Parkinson's disease (PD), Lewy body dementia (LBD), and other synucleinopathies. It is mainly involved in the regulation of synaptic vesicle trafficking but can also control mitochondrial/endoplasmic reticulum (ER) homeostasis, lysosome/phagosome function, and cytoskeleton organization. Recent evidence supports that the pathological forms of α-synuclein can also reduce the release of vasoactive and inflammatory mediators from endothelial cells (ECs) and modulates the expression of tight junction (TJ) proteins important for maintaining the blood–brain barrier (BBB). This hints that α-synuclein deposition can affect BBB integrity. Border associated macrophages (BAMs) are brain resident macrophages found in association with the vasculature (PVMs), meninges (MAMs), and choroid plexus (CPMs). Recent findings indicate that these cells play distinct roles in stroke and neurodegenerative disorders. Although many studies have addressed how α-synuclein may modulate microglia, its effect on BAMs has been scarcely investigated. This review aims at summarizing the main findings supporting how α-synuclein can affect ECs and/or BAMs function as well as their interplay and effect on other cells in the brain perivascular environment in physiological and pathological conditions. Gaps of knowledge and new perspectives on how this protein can contribute to neurodegeneration by inducing BBB homeostatic changes in different neurological conditions are highlighted.

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Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson’s disease

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01136-3 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Juan F. Reyes ◽

Sara Ekmark-Léwen ◽

Marina Perdiki ◽

Therése Klingstedt ◽

Alana Hoffmann ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Potential Role ◽

Alpha Synuclein ◽

Wild Type ◽

Junction Protein ◽

The Central Nervous System ◽

Gap Junction Protein ◽

First Time ◽

The Brain

AbstractAlpha-synuclein (α-syn) aggregation is the hallmark pathological lesion in brains of patients with Parkinson’s disease (PD) and related neurological disorders characterized as synucleinopathies. Accumulating evidence now indicates that α-syn deposition is also present within the gut and other peripheral organs outside the central nervous system (CNS). In the current study, we demonstrate for the first time that α-syn pathology also accumulates within the liver, the main organ responsible for substance clearance and detoxification. We further demonstrate that cultured human hepatocytes readily internalize oligomeric α-syn assemblies mediated, at least in part, by the gap junction protein connexin-32 (Cx32). Moreover, we identified a time-dependent accumulation of α-syn within the liver of three different transgenic (tg) mouse models expressing human α-syn under CNS-specific promoters, despite the lack of α-syn mRNA expression within the liver. Such a brain-to-liver transmission route could be further corroborated by detection of α-syn pathology within the liver of wild type mice one month after a single striatal α-syn injection. In contrast to the synucleinopathy models, aged mice modeling AD rarely show any amyloid-beta (Aß) deposition within the liver. In human post-mortem liver tissue, we identified cases with neuropathologically confirmed α-syn pathology containing α-syn within hepatocellular structures to a higher degree (75%) than control subjects without α-syn accumulation in the brain (57%). Our results reveal that α-syn accumulates within the liver and may be derived from the brain or other peripheral sources. Collectively, our findings indicate that the liver may play a role in the clearance and detoxification of pathological proteins in PD and related synucleinopathies.

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High-Affinity Detection of Alpha-Synuclein by Aptamer-Gold Conjugates on an Amine-Modified Dielectric Surface

Journal of Analytical Methods in Chemistry ◽

10.1155/2019/6526850 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Xuemei You ◽

Subash C. B. Gopinath ◽

Thangavel Lakshmipriya ◽

Dingan Li

Keyword(s):

Limit Of Detection ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Dielectric Surface ◽

Interdigitated Electrode ◽

High Affinity ◽

Modified Surfaces ◽

The Central Nervous System ◽

Related Proteins ◽

The Brain

Parkinson’s disease (PD) is a progressive health issue and influences an increasingly larger number of people, especially at older ages, affecting the central nervous system (CNS). Alpha-synuclein is a biomarker closely correlated with the CNS and PD. The loss of neuronal cells in the substantia nigra leads to the aggregation of alpha-synuclein in the form of Lewy bodies, and Lewy neuritis is a neuropathological hallmark. The therapeutic approach of PD focuses on alpha-synuclein as an important substrate of PD pathology. So far, research has focused on antialpha-synuclein to minimize the burden of extracellular alpha-synuclein in the brain, and as a consequence, it ameliorates inflammation. Interdigitated electrode (IDE) biosensors are efficient tools for detecting various analytes and were chosen in this study to detect alpha-synuclein on amine-modified surfaces by using antiaptamer-alpha-synuclein as the probe. In addition, a gold nanoparticle-conjugated aptamer was used to enhance the detection limit. The limit of detection for the binding between alpha-synuclein and aptamer was found to be 10 pM. Control experiments were performed with two closely related proteins, amyloid-beta and tau, to reveal the specificity; the results show that the aptamer only recognized alpha-synuclein. The proposed strategy helps to identify the binding of aptamer and alpha-synuclein and provides a possible method to lower alpha-synuclein levels and inflammation in PD patients.

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Synthesis of Alginate-Curcumin Nanocomposite and Its Protective Role in Transgenic Drosophila Model of Parkinson’s Disease

ISRN Pharmacology ◽

10.1155/2013/794582 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 23

Author(s):

Yasir Hasan Siddique ◽

Wasi Khan ◽

Braj Raj Singh ◽

Alim H. Naqvi

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Lewy Bodies ◽

Protective Role ◽

Alpha Synuclein ◽

Lower Permeability ◽

Normal Human ◽

Climbing Ability ◽

The Brain

The genetic models in Drosophila provide a platform to understand the mechanism associated with degenerative diseases. The model for Parkinson's disease (PD) based on normal human alpha-synuclein (αS) expression was used in the present study. The aggregation of αS in brain leads to the formation of Lewy bodies and selective loss of dopaminergic neurons due to oxidative stress. Polyphenols generally have the reduced oral bioavailability, increased metabolic turnover, and lower permeability through the blood brain barrier. In the present study, the effect of synthesized alginate-curcumin nanocomposite was studied on the climbing ability of the PD model flies, lipid peroxidation, and apoptosis in the brain of PD model flies. The alginate-curcumin nanocomposite at final doses of 10−5, 10−3, and 10−1 g/mL was supplemented with diet, and the flies were allowed to feed for 24 days. A significant dose-dependent delay in the loss of climbing ability and reduction in the oxidative stress and apoptosis in the brain of PD model flies were observed. The results suggest that alginate-curcumin nanocomposite is potent in delaying the climbing disability of PD model flies and also reduced the oxidative stress as well as apoptosis in the brain of PD model flies.

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Aging exacerbates the brain inflammatory micro-environment contributing to α-synuclein pathology and functional deficits a mouse model of DLB/PD

10.21203/rs.3.rs-211252/v1 ◽

2021 ◽

Author(s):

Michiyo Iba ◽

Ross McDevitt ◽

Changyoun Kim ◽

Roshni Roy ◽

Dimitra Sarantopoulou ◽

...

Keyword(s):

Mouse Model ◽

Immune Responses ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Behavioral Deficits ◽

Inflammatory Gene Expression ◽

Functional Deficits ◽

Age Related ◽

The Brain

Abstract ɑ-synuclein (ɑ-syn) progressively accumulates in age related neurodegenerative diseases such as Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). Although ɑ-syn spreading has been extensively investigated, the role of aging in the manifestation of disease remains unclear. Thus, we explored the role of aging in the pathogenesis of synucleinopathies in a mouse model of DLB/PD initiated by intrastiatal injection of ɑ-syn preformed fibrils (pff). We found that aged mice showed more extensive accumulation of ɑ-syn and behavioral deficits that was associated with greater infiltration of T cells and microgliosis. Microglial inflammatory gene expression induced by ɑ-syn-pff injection in young mice had hallmarks of aged microglia, indicating that enhanced age-associated pathologies may result from inflammatory synergy between aging and the effects of ɑ-syn aggregation. We propose that aging related inflammation influences outcomes of pathological spreading of ɑ-syn and suggests that targeting immune responses might be important in developing treatments for DLB/PD.

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