scholarly journals Functions of Intracellular Alpha-Synuclein in Microglia: Implications for Parkinson’s Disease Risk

2021 ◽  
Vol 15 ◽  
Author(s):  
Alix Booms ◽  
Gerhard A. Coetzee
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Risk ◽  
Significant Risk ◽  
Physiological Role ◽  
Significant Risk Factor ◽  
Cell Types ◽  
Alpha Synuclein ◽  
Vesicle Formation ◽  
Immune Functions

Alpha-synuclein accumulation in dopaminergic neurons is one of the primary features of Parkinson’s disease (PD). Despite its toxic properties during PD, alpha-synuclein has some important physiological functions. Although the activity of the protein has been extensively studied in neurons, the protein is also expressed in other cell types including immune cells and glia. Genetic studies show that mutations in synuclein alpha (SNCA), the gene that encodes alpha-synuclein, and alterations in its expression levels are a significant risk factor for PD, which likely impact the functions of a broad range of cell types. The consequences of altered SNCA expression in other cell types is beginning to be explored. Microglia, the primary macrophage population in the Central Nervous System (CNS), for example, are affected by variations in alpha-synuclein levels and functions. Studies suggest that deviations of alpha-synuclein’s normal activity influence hematopoiesis, the process that gives rise to microglia, and microglia’s immune functions. Alpha-synuclein levels also dictate the efficiency of SNARE-mediated vesicle formation, which could influence autophagy and cytokine release in microglia. Starting from the time of conception, these effects could impact one’s risk for developing PD. Further studies are needed to determine the physiological role of alpha-synuclein and how the protein is affected during PD in non-neuronal cells such as microglia. In this review we will discuss the known roles of alpha-synuclein in differentiation, immune responses, and vesicle formation, with insights into how abnormal alpha-synuclein expression and activity are linked to altered functions of microglia during PD.

scholarly journals Heritability enrichment implicates microglia in Parkinson’s disease pathogenesis

2020 ◽  
Author(s):  
Maren Stolp Andersen ◽  
Sara Bandres-Ciga ◽  
Regina H. Reynolds ◽  
John Hardy ◽  
Mina Ryten ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Risk ◽  
Association Studies ◽  
Cell Types ◽  
Polygenic Risk Score ◽  
Open Chromatin ◽  
Specific Cell ◽  
Genome Wide Association Studies ◽  
Therapeutic Implications

AbstractObjectiveUnderstanding how different parts of the immune system contribute to pathogenesis in Parkinson’s disease is a burning challenge with important therapeutic implications. We studied enrichment of common variant heritability for Parkinson’s disease stratified by immune and brain cell types.MethodsWe used summary statistics from the most recent meta-analysis of genome-wide association studies in Parkinson’s disease and partitioned heritability using linkage disequilibrium score regression, stratified for specific cell types as defined by open chromatin regions. We also validated enrichment results using a polygenic risk score approach and intersected disease-associated variants with epigenetic data and expression quantitative loci to nominate and explore a putative microglial locus.ResultsWe found significant enrichment of Parkinson’s disease risk heritability in open chromatin regions of microglia and monocytes. Genomic annotations overlapped substantially between these two cell types, and only the enrichment signal for microglia remained significant in a joint model. We present evidence suggesting P2RY12, a key microglial gene and target for the anti-thrombotic agent clopidogrel, as the likely driver of a significant Parkinson’s disease association signal on chromosome 3.InterpretationOur results provide further support for the importance of immune mechanisms in PD pathogenesis, highlight microglial dysregulation as a contributing etiological factor and nominate a targetable microglial gene candidate as a pathogenic player. Immune processes can be modulated by therapy, with potentially important clinical implications for future treatment in Parkinson’s disease.

Parkinson's disease and psychosis: Report of a case

2017 ◽  
Vol 41 (S1) ◽  
pp. s843-s844
Author(s):  
M. Valverde Barea ◽  
A. España Osuna ◽  
F. Cartas Moreno
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Family Background ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Behavioral Disorder ◽  
Psychotic Symptoms ◽  
Psychiatric Clinic ◽  
Good Tolerance ◽  
Competing Interest

IntroductionJealous delusional ideation appears in 7-14% of cases of Parkinson's disease. Treatment with dopaminomimetics drugs is a significant risk factor for psychosis. However, the most likely etiology of psychosis in these patients is a loss of central cholinergic function associated with age since described psychosis even before the introduction of the L-Dopamine. Cognitive impairment and sleep disorders are predictors of development of psychosis.ObjectivePresent a clinical case of psychosis in Parkinson's disease and its treatment.MethodReason for consultation. Patient diagnosed with Parkinson's disease with behavioral disorder and delusional.Current illnessThe patient after antiparkinsonian medication has increased suspicion, self-referentiality, delusional jealousy ideation to her husband, delusional interpretations regarding somatic symptoms, insomnia and behavioral disorders with aggression.Family backgroundMother with Alzheimer's.Personal historyNo contact with mental health.Psychopathological examinationConscious, repetitive language, dysphoric mood with delusions of prejudice and jealousy.Mixed insomnia.DiagnosisPsychosis in Parkinson's disease.TreatmentQuetiapine 300 mg/day. Carbidopa 25 mg/L-dopa 100 mg: 1-0-1. On subsequent visits quetiapine was suspended and replaced by clozapine 200 mg/day.ResultsThe treatment of psychosis was effective with the use of quetiapine and subsequently clozapine with good tolerance and effectiveness. He also said lower antiparkinsonian medication.ConclusionsPsychotic symptoms are the most common psychiatric clinic in Parkinson's disease. Often not enough antiparkinsonian dopaminomimetics reduced to control psychotic symptoms and use of antipsychotics is required. The use of antipsychotics in Parkinson's disease should be careful for the likely increase in motor clinical and increased mortality. The most useful, are especially quetiapine and clozapine atypical antipsychotics.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Alpha-synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome

Biology Open ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. bio054338
Author(s):  
Anila Iqbal ◽  
Marta Baldrighi ◽  
Jennifer N. Murdoch ◽  
Angeleen Fleming ◽  
Christopher J. Wilkinson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Intracellular Transport ◽  
Neuronal Cell Death ◽  
Lewy Bodies ◽  
Neuronal Cell ◽  
Cell Types ◽  
Alpha Synuclein ◽  
Microtubule Network ◽  
Main Component

ABSTRACTProtein aggregates are the pathogenic hallmarks of many different neurodegenerative diseases and include the accumulation of α-synuclein, the main component of Lewy bodies found in Parkinson's disease. Aggresomes are closely-related, cellular accumulations of misfolded proteins. They develop in a juxtanuclear position, adjacent to the centrosome, the microtubule organizing centre of the cell, and share some protein components. Despite the long-standing observation that aggresomes/Lewy bodies and the centrosome sit side-by-side in the cell, no studies have been done to see whether these protein accumulations impede organelle function. We investigated whether the formation of aggresomes affected key centrosome functions: its ability to organise the microtubule network and to promote cilia formation. We find that when aggresomes are present, neuronal cells are unable to organise their microtubule network. New microtubules are not nucleated and extended, and the cells fail to respond to polarity cues. Since neurons are polarised, ensuring correct localisation of organelles and the effective intracellular transport of neurotransmitter vesicles, loss of centrosome activity could contribute to functional deficits and neuronal cell death in Parkinson's disease. In addition, we provide evidence that many cell types, including dopaminergic neurons, cannot form cilia when aggresomes are present, which would affect their ability to receive extracellular signals.

scholarly journals Golf as a Physical Activity to Potentially Reduce the Risk of Falls in Older Adults with Parkinson’s Disease

Sports ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 72
Author(s):  
Rebecca R. Bliss ◽  
Frank C. Church
Keyword(s):  
Older Adults ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Advanced Age ◽  
Golf Club ◽  
Increased Risk ◽  
Risk Of Falls

Advanced age is associated with an increased risk for falls in aging adults. Older adults are also more likely to be diagnosed with Parkinson’s disease (PD), with advanced age as the most significant risk factor. PD is a neurodegenerative disorder with four Cardinal motor symptoms: rigidity, bradykinesia, postural instability, and tremor. Thus, people (person)-with-Parkinson’s disease (PwP) have an even greater risk of falling than non-disorder age-matched peers. Exercise is an activity requiring physical effort, typically carried out to sustain or improve overall health and fitness, and it lowers the risk of falls in the general population. The sport of golf provides a low-impact all-around workout promoting a range of motion, activation of muscles in the upper and lower body, flexibility, and balance. Swinging a golf club offers a unique combination of high amplitude axial rotation, strengthening postural musculature, coordination, and stabilization, demonstrating the potential to impact PD symptoms positively. Golf may be a novel exercise treatment regimen for PD to use in conjunction with traditional medical therapy. We completed a literature review to determine the relationship between the game of golf, PD, and the risk of falls. We concluded that regularly playing golf can lower the risk for falls in community ambulating older adults with PD and demonstrates the potential to improve quality of life for PwP.

scholarly journals Integration of functional genomics data to uncover cell type-specific pathways affected in Parkinson's disease

2021 ◽  
Author(s):  
Viola Volpato
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Disease Risk ◽  
Late Onset ◽  
Alpha Synuclein ◽  
Biological Information ◽  
Cell Type ◽  
Risk Variants ◽  
Cell Type Specific

Parkinson's disease (PD) is the second most prevalent late-onset neurodegenerative disorder worldwide after Alzheimer's disease for which available drugs only deliver temporary symptomatic relief. Loss of dopaminergic neurons (DaNs) in the substantia nigra and intracellular alpha-synuclein inclusions are the main hallmarks of the disease but the events that cause this degeneration remain uncertain. Despite cell types other than DaNs such as astrocytes, microglia and oligodendrocytes have been recently associated with the pathogenesis of PD, we still lack an in-depth characterisation of PD-affected brain regions at cell-type resolution that could help our understanding of the disease mechanisms. Nevertheless, publicly available large-scale brain-specific genomic, transcriptomic and epigenomic datasets can be further exploited to extract different layers of cell type-specific biological information for the reconstruction of cell type-specific transcriptional regulatory networks. By intersecting disease risk variants within the networks, it may be possible to study the functional role of these risk variants and their combined effects at cell type- and pathway levels, that, in turn, can facilitate the identification of key regulators involved in disease progression, which are often potential therapeutic targets.

scholarly journals Frequency and predictors of potential drug: Drug interactions in hospitalized patients with Parkinson's diseases

2021 ◽  
Vol 8 (3) ◽  
pp. 1099-1108
Author(s):  
Dejan Aleksić ◽  
Srđan Stefanović ◽  
Miloš Milosavljević ◽  
Jovana Milosavljević ◽  
Slobodan Janković
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Interactions ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Hospitalized Patients ◽  
Elderly Persons ◽  
Potential Drug ◽  
Cross Sectional ◽  
Parkinson’S Diseases

Introduction: Patients with Parkinson's disease are exposed to higher number of drugs on average than other elderly persons. Levodopa, of the mainstay of Parkinson's disease therapy, is frequently interacting with numerous drugs. Aim: The aim of this study was to identify predictors of potential drug-drug interactions (pDDIs) in hospitalized patients suffering from Parkinson's disease (PD). Material and Methods: This was a academic retrospective cross-sectional study in PD patients hospitalized at the Clinic of Neurology, Clinical Center Kragujevac. Medical records of hospitalized patients during the period 1.1.2017 - 31.12.2019 were analysed. The pDDIs were identified by means of Micromedex andLexi-Interact online softwares, and multivariate regression methods were used to reveal potential predictors of number of pDDIs per patient. Results: Micromedex detected 160 different pDDIs in 77.8% of 72 patients with PD. The most frequent pDDIs were those that involved aspirin (with bisoprolol, sertraline and perindopril). Predictors of pDDIs in general was total number of drugs, while use of antidepressants presented a significant risk factor for major pDDIs. Lexi-Interact revealed 310 pDDIs in 98.6% of patients. The three most common pDDIs were with levodopa (bisoprolol, clonazepam, perindopril). Total number of drugs, number of co-morbidities, hospitalization at the neurodegenerative ward, and use of antipsychotics were identified as the relevant predictors of pDDIs. Lexi-interact software detected significantly more pDDIs than Micromedex (p<0.001). Conclusion: Neurologists should pay special attention when deciding whether to administer new drug to a PD patient with multiple comorbidities, hospitalized in a neurodegenerative ward and/or taking antidepressant or antipsychotic drugs.

scholarly journals Alpha synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome

2019 ◽  
Author(s):  
Anila Iqbal ◽  
Marta Baldrighi ◽  
Jennifer N. Murdoch ◽  
Angeleen Fleming ◽  
Christopher J. Wilkinson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Intracellular Transport ◽  
Neuronal Cell Death ◽  
Lewy Bodies ◽  
Neuronal Cell ◽  
Cell Types ◽  
Alpha Synuclein ◽  
Microtubule Network

AbstractProtein aggregates are the pathogenic hallmarks of many different neurodegenerative diseases and include the Lewy bodies found in Parkinson’s disease. Aggresomes are closely-related cellular accumulations of misfolded proteins. They develop in a juxtanuclear position, adjacent to the centrosome, the microtubule organizing centre of the cell, and share some protein components. Despite the long-standing observation that aggresomes/Lewy bodies and the centrosome sit side-by-side in the cell, no studies have been done to see whether these protein accumulations impede the organelle function. We investigated whether the formation of aggresomes affected key centrosome functions: its ability to organize the microtubule network and to promote cilia formation. We find that when aggresomes are present, neuronal cells are unable to organise their microtubule network. New microtubules are not nucleated and extended, and the cells fail to respond to polarity cues. Since dopaminergic neurons are polarised, ensuring correct localisation of organelles and the effective intracellular transport of neurotransmitter vesicles, loss of centrosome activity could contribute to loss of dopaminergic function and neuronal cell death in Parkinson’s disease. In addition, we provide evidence that many cell types, including dopaminergic neurons, cannot form cilia when aggresomes are present, which would affect their ability to receive extracellular signals.

scholarly journals A Potential Innovative Therapy for Parkinson’s Disease: Selective Destruction of the Pathological Assemblies of Alpha-Synuclein

2021 ◽  
Author(s):  
Judit Oláh ◽  
Attila Lehotzky ◽  
Tibor Szénási ◽  
Judit Ovádi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Targets ◽  
Cell Types ◽  
Alpha Synuclein ◽  
Economic Problem ◽  
Innovative Therapy ◽  
New Strategy ◽  
Conformational Plasticity ◽  
Unique Specificity

With the aging of the population, Parkinson’s disease poses a serious socio-economic problem; there is no effective therapy that can arrest/revert the progression of the disease. The hallmarks of Parkinson’s disease and other synucleinopathies are the disordered alpha-synuclein and TPPP/p25. These proteins have neomorphic moonlighting characteristics by displaying both physiological and pathological functions. Physiologically TPPP/p25 regulates the dynamics/stability of the microtubules and is crucial for oligodendrocyte differentiation; while alpha-synuclein is involved in neuronal plasticity modulation and synaptic vesicle pool maintenance. In healthy brain, alpha-synuclein and TPPP/p25 occur predominantly in neurons and oligodendrocytes, respectively; however, they are co-enriched and co-localized in both cell types in brain inclusions in the cases of Parkinson’s disease and multiple system atrophy, respectively. The pathomechanisms of these diseases are largely unknown; the fatal species are the small, soluble homo- and hetero-associations of alpha-synuclein. These proteins with their high conformational plasticity and chameleon feature are challenging drug targets. Nevertheless, the contact surface of TPPP/p25-alpha-synuclein assemblies has been validated as a specific drug target. This new strategy with innovative impact, namely targeting the interface of the TPPP/p25-alpha-synuclein complex, could contribute to the development of anti-Parkinson drugs with unique specificity.

scholarly journals The subcellular arrangement of alpha-synuclein proteoforms in the Parkinson’s disease brain as revealed by multicolor STED microscopy

2021 ◽  
Author(s):  
Tim E. Moors ◽  
Christina A. Maat ◽  
Daniel Niedieker ◽  
Daniel Mona ◽  
Dennis Petersen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
High Resolution ◽  
Physiological Role ◽  
Alpha Synuclein ◽  
Stimulated Emission ◽  
Disease Stage ◽  
Post Mortem ◽  
Label Free ◽  
Sted Microscopy

AbstractVarious post-translationally modified (PTM) proteoforms of alpha-synuclein (aSyn)—including C-terminally truncated (CTT) and Serine 129 phosphorylated (Ser129-p) aSyn—accumulate in Lewy bodies (LBs) in different regions of the Parkinson’s disease (PD) brain. Insight into the distribution of these proteoforms within LBs and subcellular compartments may aid in understanding the orchestration of Lewy pathology in PD. We applied epitope-specific antibodies against CTT and Ser129-p aSyn proteoforms and different aSyn domains in immunohistochemical multiple labelings on post-mortem brain tissue from PD patients and non-neurological, aged controls, which were scanned using high-resolution 3D multicolor confocal and stimulated emission depletion (STED) microscopy. Our multiple labeling setup highlighted a consistent onion skin-type 3D architecture in mature nigral LBs in which an intricate and structured-appearing framework of Ser129-p aSyn and cytoskeletal elements encapsulates a core enriched in CTT aSyn species. By label-free CARS microscopy we found that enrichments of proteins and lipids were mainly localized to the central portion of nigral aSyn-immunopositive (aSyn+) inclusions. Outside LBs, we observed that 122CTT aSyn+ punctae localized at mitochondrial membranes in the cytoplasm of neurons in PD and control brains, suggesting a physiological role for 122CTT aSyn outside of LBs. In contrast, very limited to no Ser129-p aSyn immunoreactivity was observed in brains of non-neurological controls, while the alignment of Ser129-p aSyn in a neuronal cytoplasmic network was characteristic for brains with (incidental) LB disease. Interestingly, Ser129-p aSyn+ network profiles were not only observed in neurons containing LBs but also in neurons without LBs particularly in donors at early disease stage, pointing towards a possible subcellular pathological phenotype preceding LB formation. Together, our high-resolution and 3D multicolor microscopy observations in the post-mortem human brain provide insights into potential mechanisms underlying a regulated LB morphogenesis.

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