Thursday, September 22, 2022
Thursday, September 22, 2022
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Alpha Synuclein Parkinson’s Disease

Asyn In Exosomes/extracellular Vesicles In Body Fluids As Biomarkers Of Pd

Parkinsons Disease Pathophysiology: A Focus on Alpha-Synuclein

The cell-to-cell propagation of aSyn has been implicated as a central process in aSyn pathology spreading and PD progression, although the exact mechanisms regulating this process remain a subject of active research,. Given their presence in biological fluids and their important role in cell-cell communication, extracellular vesicles have emerged as possible candidates for regulating the cell-to-cell transfer of aSyn and pathology spreading. Furthermore, several proteins involved in proteinopathies have also been found in EVs,,. Therefore, several studies pursued EVs -derived aSyn as a potential diagnostic biomarker for PD.

Exosomes are EVs produced by different types of cells, have diameters ranging from 50 to 100nm, and contain a complex mixture of molecules, including proteins, lipids, and nucleic acids. Their secretion, transfer from one cell to another, and ability to cross the blood-brain barrier and move between the brain and systemic circulation make EVs central players in cell-to-cell communication in health and disease. They can transport and spread both physiological and pathological molecules, including toxic and seeding competent protein aggregates such as aSyn. For example, microglial exosomes facilitate aSyn cell-to-cell transfer and pathology formation. Interaction between aSyn and cell-derived exosomes has also been reported to accelerate aSyn aggregation in vitro.

Asyn In Body Fluids And Peripheral Tissues

The discovery that aSyn is readily secreted into extracellular spaces and can be found in different forms in body fluids such as CSF,,,,,,,,, blood components,,,,,,,,,,, saliva,,, and tears, as well as in peripheral tissues ,,, sparked even greater excitement about aSyn biomarkers. The diversity of peripheral sources of aSyn presents unique opportunities to develop noninvasive diagnostic and prognostic tools based on measuring the levels of individual or multiple aSyn species .

Fig. 1: Overview of the localization of aSyn in the human body.

Expression of aSyn has been detected in brain tissue, in peripheral tissues as well as in biological fluids. Specifically, in body fluids , aSyn is circulated both as a free protein and/or exosomes-inbound protein. Created with BioRender.com.

Although various biomarker-based studies have been performed to detect and quantify different aSyn species levels ,,, there is not yet a consensus on which form represent reliable biomarker for early diagnosis, patient stratification or monitoring of disease progression.

Neurotoxic Effect Of As In Pd

AS may not form pores in membranes or induce damage by itself but enlarges previous membrane defects instead. The synphilin-1 proteins have been found to be accumulated abnormally in AS inclusions of synucleopathies . AS and neuroinflammation mediated by the inflammatory response through microglial activation have been suggested to potentiate each other. Misfolded AS may activate microglia by increased expression of TNF-α, IL-1β, IL-6, iNOS, and COX-2. Following stimulation by AS, receptors as well as signaling molecules have been proposed to join the microglial response to activate signaling pathways . These pathways further contribute to PD progression .

Info graph elucidating the various repercussions that can be observed in a neuron during PD.

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Unraveling The Mechanisms Of Alpha Synuclein In Parkinson Disease

The abnormal clumping and accumulation of alpha synuclein has been shown to cause and spread dysfunction in cells, leading some to characterize Parkinson disease by proteinopathy or as a protein disease.

The abnormal clumping and accumulation of alpha synuclein, a protein suggested to have a central role in the pathogenesis of Parkinson disease , has been shown to cause and spread dysfunction in cells, leading some to characterize PD by proteinopathy or as a protein disease, said Nicki Niemann, MD, neurologist at the Muhammad Ali Parkinson Center and an assistant professor of neurology at Barrow Neurological Institute.

Transcript

AJMC®: Hello, I’m Matthew Gavidia. Today on the MJH Life Sciences Medical World News, The American Journal of Managed Care® is pleased to welcome Dr Nicki Niemann, neurologist at the Muhammad Ali Parkinson Center and an assistant professor of neurology at Barrow Neurological Institute. Dr Niemann additionally served as a co-author of a review article titled Parkinson Disease and Skin.

Alpha synuclein, an abnormal protein suggested to have a central role in the pathogenesis of parkinson disease, has been found to be present in the peripheral tissue, notably the skin. Can you discuss the mechanisms behind this protein and the diagnostic role this may have in parkinson disease?

What Disease Is Caused By Alpha

Alpha-synuclein is the major constituent of Lewy bodies and a pathogenic hallmark of all synucleinopathathies, including Parkinsons disease , dementia with Lewy bodies , and multiple system atrophy .

How does alpha-synuclein affect dopamine?

-Synuclein has been shown to regulate the production of dopamine in cultured cells through its interaction with tyrosine hydroxylase , the rate-limiting enzyme responsible for converting tyrosine to L-3,4-dihydroxyphenylalanine in the dopamine synthesis pathway .

Which neurotransmitter may contribute to Parkinsons disease?

Parkinsons disease symptoms mainly result from low or falling levels of dopamine , a neurotransmitter. It happens when cells that produce dopamine die in the brain. Dopamine plays a role in sending messages to the part of the brain that controls movement and coordination.

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Does Gaba Help Parkinsons

We conclude that cortical GABA plays a beneficial rather than a detrimental role in Parkinsons disease, and that GABA depletion may contribute to increased motor symptom expression.

Why does alpha-synuclein aggregation?

Impairments in mitochondrial function or an increase in oxidative stress can induce protein modifications that facilitate the conversion of -synuclein to a fibrillar pathway. Changes in membrane composition or changes in expression of binding partners can initiate -synuclein aggregation.

How do Lewy bodies cause Parkinsons?

When the accumulation of Lewy bodies blocks dopamines production and transmission, the result is the hallmark movement issues of Parkinsons disease. Acetylcholine: This neurotransmitter does its work in the parts of the brain responsible for memory, thinking and processing.

Proneurogenic Function Of Alpha

In some neurodegenerative diseases, alpha-synuclein produces insoluble inclusion bodies. These diseases, known as synucleinopathies, are connected with either higher levels of normal alpha-synuclein or its mutant variants. The normal physiological role of Snca, however, has not yet been thoroughly explained. In fact, physiological Snca has been demonstrated to have a neuroprotective impact by inhibiting apoptosis induced by several types of apoptotic stimuli, or by regulating the expression of proteins involved in apoptotic pathways.Recently it has been demonstrated that up-regulation of alpha-synuclein in the dentate gyrus activates stem cells, in a model of premature neural aging. This model shows reduced expression of alpha-synuclein and reduced proliferation of stem cells, as is physiologically observed during aging. Exogenous alpha-synuclein in the dentate gyrus is able to rescue this defect. Moreover, alpha-synuclein also boosts the proliferation of dentate gyrus progenitor neural cells in wild-type young mice. Thus, alpha-synuclein represents an effector for neural stem and progenitor cell activation.Similarly, alpha-synuclein has been found to be required to maintain stem cells of the SVZ in a cycling state.

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Pathways Implicated In Toxicity Of

Disruption of several cellular pathways leads to the loss of dopaminergic neurons in PD, including synaptic vesicle recycling, mitochondrial function, oxidative stress, endoplasmic reticulum stress, and autophagy-lysosomal pathway function . The accumulation of -syn into prefibrillar forms, and then its assembly into higher molecular weight aggregates, induces cellular toxicity and maybe the greatest contributor to pathogenesis in PD . The increased cellular toxic burden caused by aggregated -syn may arise from overexpression of the protein, genetic multiplication, or impairment to normal protein clearance mechanisms such as autophagy .

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TWiN 30: Gut to brain spread of alpha-synuclein in Parkinson’s disease

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Overview About The Amyloidosis In Neurodegenerative Disorders

The pathological commonality among predominant neurodegenerative disorders such as Alzheimer’s disease , Huntington’s disease , PD, prion disorders, and amyotrophic lateral sclerosis are protein aggregation and the formation of inclusion bodies. The aggregates also called as amyloids, are composed of fibers and fibrils consisting aberrant misfolded proteins rich in beta-sheets. Amyloid deposition is directly associated with cellular deterioration and neuronal malfunction. It is also insinuated to effectuate endoplasmic reticulum, oxidative stress, mitochondrial, and proteasomal dysfunction, thus eventually causing neuronal waning. While mutations are culpable behind protein misfolding, sporadic causes attributed to other genetic and environmental variables. Increasing reports from various studies have elucidated the better comprehension of biochemical pathways associated with protein aggregation. Chief pathways suspected to cause protein aggregation include unfolded states/unfolding intermediates mediated physical aggregation, aggregation propelled chemical linkages, or protein self-association and aggregation mediated via chemical degradations .

Parkinsons Disease And Alpha

Professor Stephan Witt is interested in the role that the protein, alpha-synuclein, plays in the development of Parkinsons disease. Together with his team at LSU Health Shreveport, USA, he has used yeast and worm models of Parkinsons disease to investigate the mechanisms and molecules that are involved in the development of disease. The hope is that with increased knowledge of how Parkinsons is caused, it will open the door to possible new therapies for patients.

Parkinsons disease affects 1-2% of the population over 65 years of age and is the most commonly occurring movement disorder. The disease is caused by selective degeneration of dopaminergic neurons in a region of the mid-brain called the substantia nigra. Although their numbers are few, these dopamine-producing neurons play an important role in the control of multiple brain functions, including voluntary movement, as well as a broad array of behavioural processes such as mood, reward, addiction, and stress. Loss of these neurons can lead to slow movement, rigidity and unstable posture. The affected neurons often show aggregates called Lewy bodies, whose main component is the protein alpha-synuclein. Although highly expressed in the brain, alpha-synuclein is also present in red blood cells, intestinal cells, liver cells and melanocytes, the cells that produce melanin.

Parkinsons disease affects 1-2% of the population over 65 years of age and is the most commonly occurring movement disorder.

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The Role Of Cellular Senescence In The Pathogenesis Of Parkinsons Disease

Brenda Knox | August 29th, 2022 | Product Citation Summary

Cellular senescence is a homeostatic biological process that functions to irreversibly halt the proliferation of dividing cell types. It has a central role in embryonic development, as well as prevents tumorigenesis and limits tissue damage following injury. However, a growing body of evidence suggests senescence to be associated with neurodegenerative disorders including Alzheimers disease, Parkinsons Disease, amyotrophic lateral sclerosis, Down syndrome, and multiple sclerosis. To investigate the role of cellular senescence in Parkinsons Disease , a team of researchers led by Dinesh Kumar Verma, Ph.D., of Delaware State University used StressMarqs -synuclein preformed fibrils to perform a series of in vitro and in vivo studies centered on monitoring the expression of known senescence markers. Their data, published in Cells, showed that -syn PFF-induced pathology could be linked to cellular senescence in PD brains, indicating senescent cells to be viable therapeutic targets.

-syn PFF induces in vitro expression of cellular senescence markers

In vivo results mirror in vitro data

Future perspectives

Supporting The Study Of Alpha Synuclein In Parkinsons Disease

Our product portfolio contains a comprehensive selection of high-quality reagents to support Parkinsons disease research. These include active human and mouse recombinant alpha synuclein pre-formed fibrils, active human recombinant A53T mutant alpha synuclein pre-formed fibrils , and dopamine HCL stabilized human recombinant alpha synuclein oligomers .

TEM of Type 1 Alpha Synuclein Preformed Fibrils .

Primary rat hippocampal neurons show Lewy body inclusion formation when treated with A53T mutant Alpha Synuclein Protein Preformed Fibrils but not when treated with a media control . Tissue: Primary hippocampal neurons. Species: Sprague-Dawley rat. Primary Antibody: Rabbit anti-pSer129 Antibody. Fibrils were diluted to 1 ug/uL in neuronal media consisting of B27, Glutamax, penicillin/strip, and neurobasalA and sonicated for 1 hour in a water bath. The sonicated stock was then used to achieve the final concentration of 1 ug/mL in the wells.

REFERENCES

  • Alpha-Synuclein in Parkinsons Disease: From Pathogenetic Dysfunction to Potential Clinical Application, Xu L and Pu J, Parkinsons Dis. 2016 2016
  • A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly, Giasson BI et al, J Biol Chem. 2001 Jan 26 276:2380-6
  • Cellular and Molecular Basis of Neurodegeneration in Parkinson Disease, Zeng XS et al, Front Aging Neurosci. 2018 Apr 17 10:109
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    Misfolding And Aggregation Of

    Misfolding and aggregation of proteins are often considered to be a consistent pathological feature of neurodegenerative disorders . In order to understand the role of -syn in mediating the pathogenesis of PD, the researchers studied -syn knockout mice and found that although they showed some defects in the nigrostriatal DA pathway, they could survive and give birth without any abnormalities or characteristics of PD . This study suggests that PD is caused by the acquisition of toxic function of -syn, not by the loss of its normal function. The gain of toxic function of -syn is related to the accumulation of -syn, which leads to its aggregation. In addition, the changes of SNCA gene expression caused by gene duplication, triplication or mutations aggravate the accumulation of misfolded -syn. This phenomenon prompted the researchers to study in detail the aggregation pathway of -syn in vitro. As a result, these studies support the hypothesis that accelerated fibrillation of -syn is the cause of early-onset PD .

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    Alpha Synuclein In Parkinsons Disease

    Christina Korgiopoulou | January 22nd, 2020 |

    Alpha synuclein is encoded by the SNCA gene, which gives rise to a 14kDa protein with an N-terminal domain , a nonamyloid-? component of plaques domain , and a C-terminal domain 1. Of these, the NAC domain makes alpha synuclein unique to the other two members of the synuclein family , providing it with the capacity to form fibrils through self-polymerization,2. Since aggregates of fibrillar alpha-synuclein define several neurodegenerative conditions, including Parkinsons disease, preventing these from developing represents a promising therapeutic approach.

    Modified Asyn Protein Standards

    Ask the MD: What Is Alpha-Synuclein?

    Initially, researchers in the field did not have access to pure protein standards of site-specifically modified aSyn proteins. Therefore, many preceding studies, aiming to quantify pS129, used aSyn protein standards that were generated by incubating recombinant aSyn with kinases that were later shown to phosphorylate aSyn only partially at S129 , thus resulting in impure protein standards,,,,,. In many of these studies, it is unclear whether the phosphorylated protein was purified or whether mixtures of unmodified and pS129 aSyn of unknown proportion were used as pS129 standards,,,,.

    The discovery of the Polo-like kinases : PLK2 and PLK3, as kinases that efficiently and quantitatively phosphorylate aSyn in vitro and in cells, made the generation of pure pS129 protein standards possible. Unfortunately, in many cases where PLK2 or PLK3 were used, the extent of aSyn S129 phosphorylation was not reported. Again, in many cases it was not described whether the pS129 aSyn proteins used were purified from the in vitro phosphorylation reaction mixture . Furthermore, in the majority of published biomarker studies, the analytical data on the purity and characterization of the protein standards used were not presented. Such data should be included in future studies to demonstrate that the protein standards used are highly pure and free of aSyn truncations, oligomers or other aggregated forms of the protein.

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    Iii A Reducing Snca Transcription

    Two biologics have also been studied as potential therapeutics for PD that act by decreasing transcription of the SNCA gene: SLS-004 and ST-502. The former, SLS-004, is a lentiviral vector containing DNA-methyltransferase 3A, which targets DNA-methylation editing within intron 1 of the SNCA gene to downregulate expression . SLS-004 treatment of human induced-pluripotent stem cells from a patient with PD with SNCA triplication led to decreased levels of -Syn mRNA and protein levels as well as reduced reactive oxygen species and increased cell viability. On the other hand, ST-502 is a zinc-finger transcription factor from Sangamo therapeutics, which is delivered by an adeno-associated virus vector and functions at the DNA level to selectively repress the expression of SNCA. Releases from the company report that ST-502 can decrease SNCA mRNA, but this work is not yet published in the scientific literature. Both of these biologics are at the preclinical stage.

    Role Of Personalized Medicine In Mitigating Pd Pathology

    Till now, PD’s heterogenic pathology has been well-delineated. Further, it paves way for the formulation of personalized therapeutics, wherein it is surmised that pathophysiology and genetic might be crucial. Due to this heterogeneity, an imperative need for developing individualized pathology mitigating therapies have been imposed upon the medical society. Recent medical advancement has made us witness, treatments effectuated upon PD patients with specific genetic aberration.

    Glucocerebrosidase is a common risk factor associated with PD. Mutations in GBA gene, which encodes glucocerebrosidase, are found predominantly among people from Netherlands and Ashkenazi Jews. Though GBA’s role in PD remains obscure, targeted therapeutics can be steered toward restoration of enzyme function and regulation of glycosphingolipid turnover. Accordingly, gene therapy though adeno-associated virus expression glucocerebrosidase has shown positive findings in GBA pre-clinical studies. And reduced levels of alpha-synuclein aggregates were also reported in the same. Further, Ambroxol is currently being investigated in a PD clinical trial.

    Like GBA, genetic mutations in LRRK2 are also prevalent in certain ethnicities and also considered to be a credible risk factor for autosomal dominant PD. Enhancing LRRK2 kinase seems to have a beneficial effect. At present, various structurally distinct LRRK2 inhibitors formulated by Merck, Pfizer, Genentech and GSK are in the pipeline.

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    V A Targeting Autophagy

    Bosutinib is another tyrosine kinase inhibitor being investigated in PD. In mice challenged with lentiviral injection of -Syn into the substantia nigra and in A53T -Syn transgenic mice, intraperitoneal injection of bosutinib decreased -Syn protein levels and markers of inflammation . Accordingly, a phase 2 trial of bosutinib at 100 mg daily for 90 days in patients with DLB is currently active and not recruiting . Trehalose is another compound that has been shown to enhance autophagy, likely through activation of transcription factor EB . Oral trehalose provided in the drinking water has been found to be protective on multiple outcome measures in a variety of animal models of PD, including in rats injected in the striatum with A53T -Syn in an AAV vector, rats lesioned with rotenone or 6-OHDA, and mice lesioned with MPTP . Human trials of trehalose for PD have not been undertaken, but phase 1 trials have been initiated in AD and spinocerebellar ataxia 3.

    Another upstream regulator of autophagy is Beclin 1. Overexpression of Beclin-1 via lentivirus vector prevented -Syn accumulation and synapse loss in the PDGF promoter driven -Syn transgenic mouse model . MicroRNA-7 also activates autophagy and may, therefore, be a potential agent for disease modification in PD through this mechanism in addition to reducing -Syn protein levels . Both overexpression of Beclin-1 and treatment with miRNA-7 are at the preclinical stage.

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