scholarly journals Bacteria, Lipopolysaccharides, Amyloid and the Role of Iron Dysregulation in Parkinson’s Disease

2020 ◽  
Author(s):  
Marthinus Janse van Vuuren ◽  
Theodore Albertus Nell ◽  
Jonathan Ambrose Carr ◽  
Douglas B Kell ◽  
Etheresia Pretorius
Keyword(s):  
Systemic Inflammation ◽  
Cell Damage ◽  
Vascular Dysfunction ◽  
Alpha Synuclein ◽  
Motor Deficits ◽  
Novel Treatments ◽  
Randomized Controlled Clinical Trials ◽  
Iron Dysregulation ◽  
Neuro Inflammation ◽  
Underlying Mechanisms

Neuronal lesions in Parkinson’s disease (PD) are commonly associated with α-synuclein (α-Syn)-induced cell damage that are present both in the central and peripheral nervous systems of patients, with the enteric nervous system also being especially vulnerable. Here we bring together evidence that the development and presence of PD depends on specific sets of interlinking factors that include neuro-inflammation, systemic inflammation, α-Syn-induced cell damage, vascular dysfunction, iron dysregulation, gut and periodontal dysbiosis. We argue that there is significant evidence that bacterial inflammagens fuel this systemic inflammation, and might be central to the development of PD. We also discuss the processes whereby lipopolysaccharides may be involved in causing nucleation of proteins, including of α-Syn. Lastly, we review evidence that pre-and probiotics, as well as antibiotics and faecal transplant treatment might be valuable treatments in PD. A most important consideration, however, is that these therapeutic options need to be validated and tested in randomized controlled clinical trials. However, targeting underlying mechanisms of PD, including gut dysbiosis and iron toxicity, have potentially opened up possibilities of a wide variety of novel treatments which may relieve the characteristic non-motor deficits of PD, and may even slow the progression and/or accompanying gut-related conditions of the disease.

scholarly journals Iron Dysregulation and Inflammagens Related to Oral and Gut Health Are Central to the Development of Parkinson’s Disease

Biomolecules ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 30
Author(s):  
Marthinus Janse van Vuuren ◽  
Theodore Albertus Nell ◽  
Jonathan Ambrose Carr ◽  
Douglas B. Kell ◽  
Etheresia Pretorius
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Systemic Inflammation ◽  
Cell Damage ◽  
Vascular Dysfunction ◽  
Iron Chelation ◽  
Gut Health ◽  
Novel Treatments ◽  
Randomized Controlled Clinical Trials ◽  
Iron Dysregulation

Neuronal lesions in Parkinson’s disease (PD) are commonly associated with α-synuclein (α-Syn)-induced cell damage that are present both in the central and peripheral nervous systems of patients, with the enteric nervous system also being especially vulnerable. Here, we bring together evidence that the development and presence of PD depends on specific sets of interlinking factors that include neuroinflammation, systemic inflammation, α-Syn-induced cell damage, vascular dysfunction, iron dysregulation, and gut and periodontal dysbiosis. We argue that there is significant evidence that bacterial inflammagens fuel this systemic inflammation, and might be central to the development of PD. We also discuss the processes whereby bacterial inflammagens may be involved in causing nucleation of proteins, including of α-Syn. Lastly, we review evidence that iron chelation, pre-and probiotics, as well as antibiotics and faecal transplant treatment might be valuable treatments in PD. A most important consideration, however, is that these therapeutic options need to be validated and tested in randomized controlled clinical trials. However, targeting underlying mechanisms of PD, including gut dysbiosis and iron toxicity, have potentially opened up possibilities of a wide variety of novel treatments, which may relieve the characteristic motor and nonmotor deficits of PD, and may even slow the progression and/or accompanying gut-related conditions of the disease.

scholarly journals EEG Fractal Analysis Reflects Brain Impairment after Stroke

Entropy ◽  
2021 ◽  
Vol 23 (5) ◽  
pp. 592
Author(s):  
Maria Rubega ◽  
Emanuela Formaggio ◽  
Franco Molteni ◽  
Eleonora Guanziroli ◽  
Roberto Di Marco ◽  
...  
Keyword(s):  
Early Stage ◽  
Brain Activity ◽  
Phase 1 ◽  
Behavioral Changes ◽  
Stroke Survivors ◽  
Eeg Signals ◽  
Novel Treatments ◽  
Fractal Measures ◽  
Underlying Mechanisms ◽  
Random Fluctuations

Stroke is the commonest cause of disability. Novel treatments require an improved understanding of the underlying mechanisms of recovery. Fractal approaches have demonstrated that a single metric can describe the complexity of seemingly random fluctuations of physiological signals. We hypothesize that fractal algorithms applied to electroencephalographic (EEG) signals may track brain impairment after stroke. Sixteen stroke survivors were studied in the hyperacute (<48 h) and in the acute phase (∼1 week after stroke), and 35 stroke survivors during the early subacute phase (from 8 days to 32 days and after ∼2 months after stroke): We compared resting-state EEG fractal changes using fractal measures (i.e., Higuchi Index, Tortuosity) with 11 healthy controls. Both Higuchi index and Tortuosity values were significantly lower after a stroke throughout the acute and early subacute stage compared to healthy subjects, reflecting a brain activity which is significantly less complex. These indices may be promising metrics to track behavioral changes in the very early stage after stroke. Our findings might contribute to the neurorehabilitation quest in identifying reliable biomarkers for a better tailoring of rehabilitation pathways.

scholarly journals In vivo electrophysiology of nigral and thalamic neurons in alpha-synuclein-overexpressing mice highlights differences from toxin-based models of parkinsonism

2013 ◽  
Vol 110 (12) ◽  
pp. 2792-2805 ◽  
Author(s):  
C. J. Lobb ◽  
A. K. Zaheer ◽  
Y. Smith ◽  
D. Jaeger
Keyword(s):  
Primary Motor Cortex ◽  
Alpha Synuclein ◽  
Motor Dysfunction ◽  
Motor Deficits ◽  
Dopamine Depletion ◽  
Wild Type ◽  
Beta Oscillations ◽  
Nigrostriatal Dopamine ◽  
6 Hydroxydopamine

Numerous studies have suggested that alpha-synuclein plays a prominent role in both familial and idiopathic Parkinson's disease (PD). Mice in which human alpha-synuclein is overexpressed (ASO) display progressive motor deficits and many nonmotor features of PD. However, it is unclear what in vivo pathophysiological mechanisms drive these motor deficits. It is also unknown whether previously proposed pathophysiological features (i.e., increased beta oscillations, bursting, and synchronization) described in toxin-based, nigrostriatal dopamine-depletion models are also present in ASO mice. To address these issues, we first confirmed that 5- to 6-mo-old ASO mice have robust motor dysfunction, despite the absence of significant nigrostriatal dopamine degeneration. In the same animals, we then recorded simultaneous single units and local field potentials (LFPs) in the substantia nigra pars reticulata (SNpr), the main basal ganglia output nucleus, and one of its main thalamic targets, the ventromedial nucleus, as well as LFPs in the primary motor cortex in anesthetized ASO mice and their age-matched, wild-type littermates. Neural activity was examined during slow wave activity and desynchronized cortical states, as previously described in 6-hydroxydopamine-lesioned rats. In contrast to toxin-based models, we found a small decrease, rather than an increase, in beta oscillations in the desynchronized state. Similarly, synchronized burst firing of nigral neurons observed in toxin-based models was not observed in ASO mice. Instead, we found more subtle changes in pauses of SNpr firing compared with wild-type control mice. Our results suggest that the pathophysiology underlying motor dysfunction in ASO mice is distinctly different from striatal dopamine-depletion models of parkinsonism.

Platelet Behavior Contributes to Neuropathologies: A Focus on Alzheimer's and Parkinson's Disease

2021 ◽  
Author(s):  
Martin J. Page ◽  
Etheresia Pretorius
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Vascular Dysfunction ◽  
Surface Receptors ◽  
Initiation Factors ◽  
Physiological Processes ◽  
Vascular Regulation ◽  
Inflammatory Mechanism ◽  
Neuro Inflammation ◽  
Neurovascular Dysfunction

AbstractThe functions of platelets are broad. Platelets function in hemostasis and thrombosis, inflammation and immune responses, vascular regulation, and host defense against invading pathogens, among others. These actions are achieved through the release of a wide set of coagulative, vascular, inflammatory, and other factors as well as diverse cell surface receptors involved in the same activities. As active participants in these physiological processes, platelets become involved in signaling pathways and pathological reactions that contribute to diseases that are defined by inflammation (including by pathogen-derived stimuli), vascular dysfunction, and coagulation. These diseases include Alzheimer's and Parkinson's disease, the two most common neurodegenerative diseases. Despite their unique pathological and clinical features, significant shared pathological processes exist between these two conditions, particularly relating to a central inflammatory mechanism involving both neuroinflammation and inflammation in the systemic environment, but also neurovascular dysfunction and coagulopathy, processes which also share initiation factors and receptors. This triad of dysfunction—(neuro)inflammation, neurovascular dysfunction, and hypercoagulation—illustrates the important roles platelets play in neuropathology. Although some mechanisms are understudied in Alzheimer's and Parkinson's disease, a strong case can be made for the relevance of platelets in neurodegeneration-related processes.

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

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.

Methylphenidate causes cytotoxicity on photoreceptor cells via autophagy

2020 ◽  
Vol 40 (1) ◽  
pp. 71-80
Author(s):  
N Kong ◽  
Y Bao ◽  
H Zhao ◽  
X Kang ◽  
X Tai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Expression ◽  
Messenger Rna ◽  
Cell Damage ◽  
Photoreceptor Cells ◽  
Cell Toxicity ◽  
Hyperactivity Disorder ◽  
Increased Risk ◽  
Gene And Protein Expression ◽  
Underlying Mechanisms

Methylphenidate (MPH) is used as the first-line treatment for attention-deficit hyperactivity disorder. However, there are concerns that this treatment may be associated with increased risk of retinal damage. This study was to investigate cytotoxicity of MPH on photoreceptor cells and explore its underlying mechanisms. MPH-caused cell toxicity was established in 661 W cells. Cytotoxicity was evaluated by 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium-bromid and lactate dehydrogenase assays. Oxidative stress was measured by the markers: glutathione (GSH) reductase, catalase, and superoxide dismutase activities as well as GSH, reactive oxygen species, and malondialdehyde levels. Gene and protein expression was detected by real-time polymerase chain reaction (PCR) and western blot, respectively. Results showed that MPH decreased 661 W cell viability, increased caspase-3/9 activities, and induced oxidative stress. Furthermore, MPH treatment increased messenger RNA (mRNA) expression of Beclin-1 and microtubule-associated protein 1A/1B-light chain 3B (LC3B) protein expression in 661 W cells, suggesting autophagy was induced. MPH treatment also upregulated p-JAK1/p-STAT1 protein expression. These data demonstrated that MPH could increase oxidative stress in photoreceptor cells to cause cell toxicity via autophagy, providing the scientific rationale for the photoreceptor cell damage caused by the MPH administration.

scholarly journals Experimental Models of Autoimmune Demyelinating Diseases in Nonhuman Primates

2017 ◽  
Vol 55 (1) ◽  
pp. 27-41 ◽  
Author(s):  
Lev Stimmer ◽  
Claire-Maëlle Fovet ◽  
Ché Serguera
Keyword(s):  
Nonhuman Primates ◽  
Rhesus Macaques ◽  
Acute Disseminated Encephalomyelitis ◽  
Experimental Models ◽  
Diagnostic Methods ◽  
Demyelinating Diseases ◽  
Protective Mechanisms ◽  
Common Marmosets ◽  
Neuro Inflammation ◽  
Underlying Mechanisms

Human idiopathic inflammatory demyelinating diseases (IIDD) are a heterogeneous group of autoimmune inflammatory and demyelinating disorders of the central nervous system (CNS). These include multiple sclerosis (MS), the most common chronic IIDD, but also rarer disorders such as acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (NMO). Great efforts have been made to understand the pathophysiology of MS, leading to the development of a few effective treatments. Nonetheless, IIDD still require a better understanding of the causes and underlying mechanisms to implement more effective therapies and diagnostic methods. Experimental autoimmune encephalomyelitis (EAE) is a commonly used animal model to study the pathophysiology of IIDD. EAE is principally induced through immunization with myelin antigens combined with immune-activating adjuvants. Nonhuman primates (NHP), the phylogenetically closest relatives of humans, challenged by similar microorganisms as other primates may recapitulate comparable immune responses to that of humans. In this review, the authors describe EAE models in 3 NHP species: rhesus macaques ( Macaca mulatta), cynomolgus macaques ( Macaca fascicularis), and common marmosets ( Callithrix jacchus), evaluating their respective contribution to the understanding of human IIDD. EAE in NHP is a heterogeneous disease, including acute monophasic and chronic polyphasic forms. This diversity makes it a versatile model to use in translational research. This clinical variability also creates an opportunity to explore multiple facets of immune-mediated mechanisms of neuro-inflammation and demyelination as well as intrinsic protective mechanisms. Here, the authors review current insights into the pathogenesis and immunopathological mechanisms implicated in the development of EAE in NHP.

scholarly journals Sodium Butyrate Protects N2a Cells against Aβ Toxicity In Vitro

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Jingxuan Sun ◽  
Boyu Yuan ◽  
Yancheng Wu ◽  
Yuhong Gong ◽  
Wenjin Guo ◽  
...  
Keyword(s):  
Sodium Butyrate ◽  
Cell Injury ◽  
Cell Damage ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Fatty Acid Salt ◽  
Cognitive Improvement ◽  
N2a Cells ◽  
Underlying Mechanisms

Alzheimer’s disease (AD) is a common neurodegenerative disease. Aβ plays an important role in the pathogenesis of AD. Sodium butyrate (NaB) is a short-chain fatty acid salt that exerts neuroprotective effects such as anti-inflammatory, antioxidant, antiapoptotic, and cognitive improvement in central nervous system diseases. The aim of this study is to research the protective effects of NaB on neurons against Aβ toxicity and to uncover the underlying mechanisms. The results showed that 2 mM NaB had a significant improvement effect on Aβ-induced N2a cell injury, by increasing cell viability and reducing ROS to reduce injury. In addition, by acting on the GPR109A receptor, NaB regulates the expression of AD-related genes such as APP, NEP, and BDNF. Therefore, NaB protects N2a cells from Aβ-induced cell damage through activating GPR109A, which provides an innovative idea for the treatment of AD.

TET2-mediated Cdkn2A DNA hydroxymethylation in midbrain dopaminergic neuron injury of Parkinson’s disease

2020 ◽  
Vol 29 (8) ◽  
pp. 1239-1252 ◽  
Author(s):  
Ting-Ting Wu ◽  
Te Liu ◽  
Xuan Li ◽  
Ya-Jing Chen ◽  
Tian-Jiao Chen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Inhibitor ◽  
Cell Damage ◽  
Epigenetic Modification ◽  
Substantia Nigra Pars Compacta ◽  
Epigenetic Therapy ◽  
Motor Deficits ◽  
Dna Hydroxymethylation

Abstract It has been reported that abnormal epigenetic modification is associated with the occurrence of Parkinson’s disease (PD). Here, we found that a ten-eleven translocation 2 (TET2), a staff of the DNA hydroxylases family, was increased in dopaminergic neurons in vitro and in vivo. Genome-wide mapping of DNA 5-hydroxymethylcytosine (5-hmC)-sequencing has revealed an aberrant epigenome 5-hmC landscape in 1-methyl-4-phenylpyridinium iodide (MPP+)-induced SH-SY5Y cells. The TET family of DNA hydroxylases could reverse DNA methylation by oxidization of 5-methylcytosine (5-mC) to 5-hmC. However, the relationship between modification of DNA hydroxymethylation and the pathogenesis of PD is not clear. According to the results of 5-hmC-sequencing studies, 5-hmC was associated with gene-rich regions in the genomes related to cell cycle, especially gene-cyclin-dependent kinase inhibitor 2A (Cdkn2A). Downregulation of TET2 expression could significantly rescue MPP+-stimulated SH-SY5Y cell damage and cell cycle arrest. Meanwhile, knockdown of Tet2 expression in the substantia nigra pars compacta of MPTP-induced PD mice resulted in attenuated MPTP-induced motor deficits and dopaminergic neuronal injury via p16 suppression. In this study, we demonstrated a critical function of TET2 in PD development via the CDKN2A activity-dependent epigenetic pathway, suggesting a potential new strategy for epigenetic therapy.

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