scholarly journals Cellular and Molecular Mediators of Neuroinflammation in the Pathogenesis of Parkinson’s Disease

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Sandeep Vasant More ◽  
Hemant Kumar ◽  
In Su Kim ◽  
Soo-Yeol Song ◽  
Dong-Kug Choi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Defense Mechanism ◽  
Neuronal Degeneration ◽  
Neuronal Damage ◽  
Normal Structure ◽  
Host Defense Mechanism ◽  
And Function ◽  
The Relationship ◽  
The Brain

Neuroinflammation is a host-defense mechanism associated with restoration of normal structure and function of the brain and neutralization of an insult. Increasing neuropathological and biochemical evidence from the brains of individuals with Parkinson’s disease (PD) provides strong evidence for activation of neuroinflammatory pathways. Microglia, the resident innate immune cells, may play a major role in the inflammatory process of the diseased brain of patients with PD. Although microglia forms the first line of defense for the neural parenchyma, uncontrolled activation of microglia may directly affect neurons by releasing various molecular mediators such as inflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-6, and IL-1β), nitric oxide, prostaglandin E2, and reactive oxygen and nitrogen species. Moreover, recent studies have reported that activated microglia phagocytose not only damaged cell debris but also intact neighboring cells. This phenomenon further supports their active participation in self-enduring neuronal damage cycles. As the relationship between PD and neuroinflammation is being studied, there is a realization that both cellular and molecular mediators are most likely assisting pathological processes leading to disease progression. Here, we discuss mediators of neuroinflammation, which are known activators released from damaged parenchyma of the brain and result in neuronal degeneration in patients with PD.

scholarly journals Insights into the multifaceted role of circular RNAs: implications for Parkinson’s disease pathogenesis and diagnosis

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Epaminondas Doxakis
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Clinical Manifestations ◽  
Alpha Synuclein ◽  
Circular Rnas ◽  
Age Related ◽  
And Function ◽  
The Brain

AbstractParkinson’s disease (PD) is a complex, age-related, neurodegenerative disease whose etiology, pathology, and clinical manifestations remain incompletely understood. As a result, care focuses primarily on symptoms relief. Circular RNAs (circRNAs) are a large class of mostly noncoding RNAs that accumulate with aging in the brain and are increasingly shown to regulate all aspects of neuronal and glial development and function. They are generated by the spliceosome through the backsplicing of linear RNA. Although their biological role remains largely unknown, they have been shown to regulate transcription and splicing, act as decoys for microRNAs and RNA binding proteins, used as templates for translation, and serve as scaffolding platforms for signaling components. Considering that they are stable, diverse, and detectable in easily accessible biofluids, they are deemed promising biomarkers for diagnosing diseases. CircRNAs are differentially expressed in the brain of patients with PD, and growing evidence suggests that they regulate PD pathogenetic processes. Here, the biogenesis, expression, degradation, and detection of circRNAs, as well as their proposed functions, are reviewed. Thereafter, research linking circRNAs to PD-related processes, including aging, alpha-synuclein dysregulation, neuroinflammation, and oxidative stress is highlighted, followed by recent evidence for their use as prognostic and diagnostic biomarkers for PD.

scholarly journals Extracellular Vesicles in Alzheimer’s and Parkinson’s Disease: Small Entities with Large Consequences

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2485
Author(s):  
Charysse Vandendriessche ◽  
Arnout Bruggeman ◽  
Caroline Van Cauwenberghe ◽  
Roosmarijn E. Vandenbroucke
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Progression ◽  
Extracellular Vesicles ◽  
Neurodegenerative Disorders ◽  
Neuronal Damage ◽  
Protein Aggregates ◽  
Pathological Changes ◽  
Associated Proteins ◽  
The Brain

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are incurable, devastating neurodegenerative disorders characterized by the formation and spreading of protein aggregates throughout the brain. Although the exact spreading mechanism is not completely understood, extracellular vesicles (EVs) have been proposed as potential contributors. Indeed, EVs have emerged as potential carriers of disease-associated proteins and are therefore thought to play an important role in disease progression, although some beneficial functions have also been attributed to them. EVs can be isolated from a variety of sources, including biofluids, and the analysis of their content can provide a snapshot of ongoing pathological changes in the brain. This underlines their potential as biomarker candidates which is of specific relevance in AD and PD where symptoms only arise after considerable and irreversible neuronal damage has already occurred. In this review, we discuss the known beneficial and detrimental functions of EVs in AD and PD and we highlight their promising potential to be used as biomarkers in both diseases.

Lack of Association of Locus Coeruleus Pathology with Orthostatic Hypotension in Parkinson’s Disease

2020 ◽  
pp. 1-5
Author(s):  
Qiang Tong ◽  
Liam Chen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Orthostatic Hypotension ◽  
Locus Coeruleus ◽  
The Elderly ◽  
Motor Symptom ◽  
Postmortem Brains ◽  
The Relationship ◽  
The Brain

Orthostatic hypotension (OH) is a common non-motor symptom in Parkinson’s disease (PD) and is linked with increased mortality risk among the elderly. Although the locus coeruleus (LC) is the major source of noradrenaline (NA) modulation in the brain, its role in the pathogenesis of OH in PD remains largely elusive. Here we examined 44 well characterized postmortem brains of PD patients and available clinical data to explore the relationship between OH and LC pathology in PD. Our results failed to indicate that the LC pathology as well as the substantia nigra pathology were robustly associated with the presence of OH in PD patients, suggesting targeting LC norepinephrinergic system alone may not be sufficient to treat OH in PD.

scholarly journals Oligomerization of Lrrk controls actin severing and α-synuclein neurotoxicity in vivo

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Souvarish Sarkar ◽  
Farah Bardai ◽  
Abby L. Olsen ◽  
Kelly M. Lohr ◽  
Ying-Yi Zhang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Degeneration ◽  
Mitochondrial Dynamics ◽  
Actin Dynamics ◽  
Human Neurons ◽  
Biochemical Analyses ◽  
And Function

Abstract Background Mutations in LRRK2 are the most common cause of familial Parkinson’s disease and typically cause disease in the context of abnormal aggregation and deposition of α-synuclein within affected brain tissue. Methods We combine genetic analysis of Lrrk-associated toxicity in a penetrant Drosophila model of wild type human α-synuclein neurotoxicity with biochemical analyses and modeling of LRRK2 toxicity in human neurons and transgenic mouse models. Results We demonstrate that Lrrk and α-synuclein interact to promote neuronal degeneration through convergent effects on the actin cytoskeleton and downstream dysregulation of mitochondrial dynamics and function. We find specifically that monomers and dimers of Lrrk efficiently sever actin and promote normal actin dynamics in vivo. Oligomerization of Lrrk, which is promoted by dominant Parkinson’s disease-causing mutations, reduces actin severing activity in vitro and promotes excess stabilization of F-actin in vivo. Importantly, a clinically protective Lrrk mutant reduces oligomerization and α-synuclein neurotoxicity. Conclusions Our findings provide a specific mechanistic link between two key molecules in the pathogenesis of Parkinson’s disease, α-synuclein and LRRK2, and suggest potential new approaches for therapy development.

Effect of Myricetin on the Loss of Dopaminergic Neurons in the Transgenic Drosophila Model of Parkinson’s Disease

2019 ◽  
Vol 14 (1) ◽  
pp. 58-64 ◽  
Author(s):  
Gulshan Ara ◽  
Mohammad Afzal ◽  
Smita Jyoti ◽  
Falaq Naz ◽  
Rahul ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Neuronal Damage ◽  
Radical Scavenging ◽  
Lewy Bodies ◽  
Dopamine Content ◽  
Drosophila Model ◽  
Dose Dependent ◽  
The Brain

Background: The formation of Lewy bodies is associated with the production of reactive oxygen species (ROS) and the neuronal damage specifically the dopaminergic neurons in the Parkinson’s disease patients. Hence any agent that could curtail the production of ROS /oxidative stress could act as a possible therapeutic agent thereby preventing the neuronal damage. </P><P> Method: In the present study, we first evaluated the antioxidant potential of myricetin by performing superoxide anion scavenging and diphenyl-picrylhydrazyl (DPPH) free radical scavenging assays. Myricetin at a final concentration of 10, 20 and 40&#181;M was mixed in diet and the PD flies were allowed to feed on it for 24 days. After 24 days of exposure, the dopamine content was estimated in brain and the immunohistochemistry was performed for the tyroxine hydroxylase activity on the brain sections from each group. </P><P> Results: Myricetin showed a dose-dependent increase in the antioxidative activity. The exposure of PD flies to 10, 20 and 40&#181;M of Myricetin not only showed a dose-dependent significant increase in the dopamine content compared to unexposed PD flies (p<0.05), but also prevented the loss of dopaminergic neurons in the brain of PD flies. </P><P> Conclusion: The results suggest that the antioxidative potential of myricetin is responsible for preventing the loss of dopaminergic neurons and dopamine content.

scholarly journals Dopaminergic neurodegeneration induced by Parkinson's disease-linked G2019S LRRK2 is dependent on kinase and GTPase activity

2020 ◽  
Vol 117 (29) ◽  
pp. 17296-17307 ◽  
Author(s):  
An Phu Tran Nguyen ◽  
Elpida Tsika ◽  
Kaela Kelly ◽  
Nathan Levine ◽  
Xi Chen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Inhibitor ◽  
Late Onset ◽  
Neuronal Damage ◽  
Preclinical Model ◽  
Gtpase Activity ◽  
Kinase Inhibition ◽  
Dopaminergic Neurodegeneration ◽  
The Brain

Mutations inleucine-rich repeat kinase 2(LRRK2) are the most common cause of late-onset, autosomal-dominant familial Parkinson’s disease (PD). LRRK2 functions as both a kinase and GTPase, and PD-linked mutations are known to influence both enzymatic activities. While PD-linked LRRK2 mutations can commonly induce neuronal damage in culture models, the mechanisms underlying these pathogenic effects remain uncertain. Rodent models containing familial LRRK2 mutations often lack robust PD-like neurodegenerative phenotypes. Here, we develop a robust preclinical model of PD in adult rats induced by the brain delivery of recombinant adenoviral vectors with neuronal-specific expression of human LRRK2 harboring the most common G2019S mutation. In this model, G2019S LRRK2 induces the robust degeneration of substantia nigra dopaminergic neurons, a pathological hallmark of PD. Introduction of a stable kinase-inactive mutation or administration of the selective kinase inhibitor, PF-360, attenuates neurodegeneration induced by G2019S LRRK2. Neuroprotection provided by pharmacological kinase inhibition is mediated by an unusual mechanism involving the robust destabilization of human LRRK2 protein in the brain relative to endogenous LRRK2. Our study further demonstrates that G2019S LRRK2-induced dopaminergic neurodegeneration critically requires normal GTPase activity, as hypothesis-testing mutations that increase GTP hydrolysis or impair GTP-binding activity provide neuroprotection although via distinct mechanisms. Taken together, our data demonstrate that G2019S LRRK2 induces neurodegeneration in vivo via a mechanism that is dependent on kinase and GTPase activity. Our study provides a robust rodent preclinical model ofLRRK2-linked PD and nominates kinase inhibition and modulation of GTPase activity as promising disease-modifying therapeutic targets.

scholarly journals Glycosphingolipids and neuroinflammation in Parkinson’s disease

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Karim Belarbi ◽  
Elodie Cuvelier ◽  
Marie-Amandine Bonte ◽  
Mazarine Desplanque ◽  
Bernard Gressier ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Studies ◽  
Molecular Mechanisms ◽  
Lewy Bodies ◽  
Inflammasome Activation ◽  
Nigrostriatal Pathway ◽  
Neurodegenerative Process ◽  
And Function ◽  
The Brain

Abstract Parkinson's disease is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons of the nigrostriatal pathway and the formation of neuronal inclusions known as Lewy bodies. Chronic neuroinflammation, another hallmark of the disease, is thought to play an important role in the neurodegenerative process. Glycosphingolipids are a well-defined subclass of lipids that regulate crucial aspects of the brain function and recently emerged as potent regulators of the inflammatory process. Deregulation in glycosphingolipid metabolism has been reported in Parkinson’s disease. However, the interrelationship between glycosphingolipids and neuroinflammation in Parkinson’s disease is not well known. This review provides a thorough overview of the links between glycosphingolipid metabolism and immune-mediated mechanisms involved in neuroinflammation in Parkinson’s disease. After a brief presentation of the metabolism and function of glycosphingolipids in the brain, it summarizes the evidences supporting that glycosphingolipids (i.e. glucosylceramides or specific gangliosides) are deregulated in Parkinson’s disease. Then, the implications of these deregulations for neuroinflammation, based on data from human inherited lysosomal glycosphingolipid storage disorders and gene-engineered animal studies are outlined. Finally, the key molecular mechanisms by which glycosphingolipids could control neuroinflammation in Parkinson’s disease are highlighted. These include inflammasome activation and secretion of pro-inflammatory cytokines, altered calcium homeostasis, changes in the blood-brain barrier permeability, recruitment of peripheral immune cells or production of autoantibodies.

scholarly journals Inflammatory Response Modulation by Vitamin C in an MPTP Mouse Model of Parkinson’s Disease

Biology ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1155
Author(s):  
Francesco De Nuccio ◽  
Antonia Cianciulli ◽  
Chiara Porro ◽  
Marianna Kashyrina ◽  
Melania Ruggiero ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Vitamin C ◽  
Neurodegenerative Diseases ◽  
Cell Activation ◽  
Defense Mechanism ◽  
Inflammatory Responses ◽  
Anti Inflammatory ◽  
The Brain ◽  
Vit C

Vitamin C (Vit C) is anutrient present in many foods, particularly citrus fruits, green vegetables, tomatoes, and potatoes. Vit C is studied for its applications in the prevention and management of different pathologies, including neurodegenerative diseases. Neuroinflammation is a defense mechanism activated by a stimulus or an insult that is aimed at the preservation of the brain by promoting tissue repair and removing cellular debris; however, persistent inflammatory responses are detrimental and may lead to the pathogenesis and progression of neurodegenerative diseases like Parkinson’s disease (PD) and Alzheimer’s disease. PD is one of the most common chronic progressive neurodegenerative disorders, and oxidative stress is one of the most important factors involved in its pathogenesis and progression.Due to this, research on antioxidant and anti-inflammatory compounds is an important target for counteracting neurodegenerative diseases, including PD. In the central nervous system, the presence of Vit C in the brain is higher than in other body districts, but why and how this occurs is still unknown. In this research, Vit C, with its anti-inflammatory and anti-oxidative properties, is studied to better understand its contribution to brain protection; in particular, we have investigated the neuroprotective effects of Vit C in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animal model of PD and its role in the modulation of neuroinflammation. First, we observed that Vit C significantly decreased the MPTP-induced loss of tyrosine hydroxylase (TH)-positive dopaminergic neuronal cells in the substantia nigra, as well as microglial cell activation and astrogliosis. Furthermore, gait and spontaneous locomotor activity, evaluated by an automated treadmill and the Open Field test, respectively, were partially ameliorated by Vit C treatment in MPTP-intoxicated animals. In relation to neuroinflammation, results show that Vit C reduced the protein and mRNA expression of inflammatory cytokines such as IL-6, TLR4, TNF-α, iNOS, and CD40, while anti-inflammatory proteins such as IL-10, CD163, TGF-β, and IL-4 increased. Interestingly, we show for the first time that Vit C reduces neuroinflammation by modulating microglial polarization and astrocyte activation. Moreover, Vit C was able to reduce NLRP3 activation, which is linked to the pathogenesis of many inflammatory diseases, including neuroinflammatory disorders. In conclusion, our study provides evidence that Vit C may represent a new promising dietary supplement for the prevention and alleviation of the inflammatory cascade of PD, thus contributing to neuroprotection.

scholarly journals Decrease in ITGA7 Levels Is Associated with an Increase in α-Synuclein Levels in an MPTP-Induced Parkinson’s Disease Mouse Model and SH-SY5Y Cells

2021 ◽  
Vol 22 (23) ◽  
pp. 12616
Author(s):  
Sangeun Han ◽  
Min Hyung Seo ◽  
Sabina Lim ◽  
Sujung Yeo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Expression Patterns ◽  
Alpha Synuclein ◽  
Control Group ◽  
Potential Association ◽  
Sirna Knockdown ◽  
The Relationship ◽  
The Brain

We investigated the potential association between integrin α7 (ITGA7) and alpha-synuclein (α-syn) in a methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) mouse model. Tyrosine hydroxylase (TH), ITGA7, and α-syn expression in the substantia nigra (SN) of the brain were observed to examine the pathological characteristics of PD. To determine the relationship between ITGA7 and PD, the expression of TH and α-syn was investigated after ITGA7 siRNA knockdown in SH-SY5Y cells. The ITGA7 microarray signal was decreased in the SN of the MPTP group, indicating reduced ITGA7 expression compared to that in the control. The expression patterns of ITGA7 in the control group and those of α-syn in the MPTP group were similar on immunohistochemical staining. Reduction in ITGA7 expression by ITGA7 siRNA administration induced a decrease in TH expression and an increase in α-syn expression in SH-SY5Y cells. The decreased expression of ITGA7 significantly decreased the expression of bcl2 and increased the bax/bcl2 ratio in SH-SY5Y cells. These results suggest that reduced ITGA7 expression may be related to increased α-syn expression and apoptosis of dopaminergic cells in an MPTP-induced PD mouse model. To the best of our knowledge, this is the first study to show an association between ITGA7 and PD.

Sign in / Sign up

Export Citation Format

Share Document