scholarly journals Central inhibition of P2Y12R differentially regulates survival and neuronal loss in MPTP-induced Parkinsonism in mice

2021 ◽  
Author(s):  
András Iring ◽  
Adrián Tóth ◽  
Mária Baranyi ◽  
Lilla Otrokocsi ◽  
László V. Módis ◽  
...  
Keyword(s):  
Disease Progression ◽  
Disease Onset ◽  
Neuronal Loss ◽  
Cell Loss ◽  
P2y12 Receptor ◽  
Mapk Activity ◽  
Central Inhibition ◽  
The Central Nervous System ◽  
And Control

AbstractParkinson’s disease (PD) is a chronic, progressive neurodegenerative condition; characterized with the degeneration of the nigrostriatal dopaminergic pathway and neuroinflammation. During PD progression, microglia, the resident immune cells in the central nervous system (CNS) display altered activity, but their role in maintaining PD development has remained unclear to date. The purinergic P2Y12 receptor (P2Y12R), which is exclusively expressed on the microglia in the CNS has been shown to regulate microglial activity and responses; however, the function of the P2Y12R in PD is unknown. Here we show that while pharmacological or genetic targeting of P2Y12R previous to disease onset augments acute mortality, these interventions protect against neurodegenerative cell loss and the development of neuroinflammation in vivo. Pharmacological inhibition of receptors during disease development reverses the symptoms of PD and halts disease progression. We found that P2Y12R regulate ROCK and p38 MAPK activity and control cytokine production. Understanding protective and detrimental P2Y12 receptor-mediated actions in the CNS may reveal novel approaches to control neuroinflammation and modify disease progression in PD.

scholarly journals In Vivo Assessment of Metabolic Abnormality in Alport Syndrome Using Hyperpolarized [1-13C] Pyruvate MR Spectroscopic Imaging

Metabolites ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 222
Author(s):  
Nguyen-Trong Nguyen ◽  
Eun-Hui Bae ◽  
Luu-Ngoc Do ◽  
Tien-Anh Nguyen ◽  
Ilwoo Park ◽  
...  
Keyword(s):  
Disease Progression ◽  
Alport Syndrome ◽  
Genetic Disorder ◽  
Lactate Production ◽  
Clinical Importance ◽  
Metabolic Imaging ◽  
Renal Metabolism ◽  
Hyperpolarized 13C ◽  
And Control

Alport Syndrome (AS) is a genetic disorder characterized by impaired kidney function. The development of a noninvasive tool for early diagnosis and monitoring of renal function during disease progression is of clinical importance. Hyperpolarized 13C MRI is an emerging technique that enables non-invasive, real-time measurement of in vivo metabolism. This study aimed to investigate the feasibility of using this technique for assessing changes in renal metabolism in the mouse model of AS. Mice with AS demonstrated a significant reduction in the level of lactate from 4- to 7-week-old, while the levels of lactate were unchanged in the control mice over time. This reduction in lactate production in the AS group accompanied a significant increase of PEPCK expression levels, indicating that the disease progression in AS triggered the gluconeogenic pathway and might have resulted in a decreased lactate pool size and a subsequent reduction in pyruvate-to-lactate conversion. Additional metabolic imaging parameters, including the level of lactate and pyruvate, were found to be different between the AS and control groups. These preliminary results suggest that hyperpolarized 13C MRI might provide a potential noninvasive tool for the characterization of disease progression in AS.

scholarly journals Coinfecting Prion Strains Compete for a Limiting Cellular Resource

2010 ◽  
Vol 84 (11) ◽  
pp. 5706-5714 ◽  
Author(s):  
Ronald A. Shikiya ◽  
Jacob I. Ayers ◽  
Charles R. Schutt ◽  
Anthony E. Kincaid ◽  
Jason C. Bartz
Keyword(s):  
Protein Misfolding ◽  
Neuronal Loss ◽  
Infectious Agent ◽  
Prion Strain ◽  
Prion Strains ◽  
The Central Nervous System ◽  
Transmissible Mink Encephalopathy ◽  
Prion Conversion ◽  
Cellular Components

ABSTRACT Prion strain interference can influence the emergence of a dominant strain from a mixture; however, the mechanisms underlying prion strain interference are poorly understood. In our model of strain interference, inoculation of the sciatic nerve with the drowsy (DY) strain of the transmissible mink encephalopathy (TME) agent prior to superinfection with the hyper (HY) strain of TME can completely block HY TME from causing disease. We show here that the deposition of PrPSc, in the absence of neuronal loss or spongiform change, in the central nervous system corresponds with the ability of DY TME to block HY TME infection. This suggests that DY TME agent-induced damage is not responsible for strain interference but rather prions compete for a cellular resource. We show that protein misfolding cyclic amplification (PMCA) of DY and HY TME maintains the strain-specific properties of PrPSc and replicates infectious agent and that DY TME can interfere, or completely block, the emergence of HY TME. DY PrPSc does not convert all of the available PrPC to PrPSc in PMCA, suggesting the mechanism of prion strain interference is due to the sequestering of PrPC and/or other cellular components required for prion conversion. The emergence of HY TME in PMCA was controlled by the initial ratio of the TME agents. A higher ratio of DY to HY TME agent is required for complete blockage of HY TME in PMCA compared to several previous in vivo studies, suggesting that HY TME persists in animals coinfected with the two strains. This was confirmed by PMCA detection of HY PrPSc in animals where DY TME had completely blocked HY TME from causing disease.

scholarly journals The C-terminal fragment of LRRK2 with the G2019S substitution increases the neurotoxicity of mutant A53T α-synuclein in dopaminergic neurons in vivo

2020 ◽  
Author(s):  
Noémie Cresto ◽  
Camille Gardier ◽  
Marie-Claude Gaillard ◽  
Francesco Gubinelli ◽  
Pauline Roost ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Neuronal Loss ◽  
Cell Loss ◽  
Kinase Domain ◽  
Alpha Synuclein ◽  
Significant Loss ◽  
Histological Evaluation ◽  
Mutant Form ◽  
G2019s Mutation

Abstract Background: Alpha-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) likely play crucial roles both in sporadic and familial forms of Parkinson’s disease (PD). The most prevalent mutation in LRRK2 is the G2019S substitution, which induces neurotoxicity through increased kinase activity. There is likely an interplay between LRRK2 and α-syn involved in the neurodegeneration of dopaminergic (DA) neurons in the substantia nigra (SNpc) in PD. However, the mechanisms underlying this interplay are ill-defined. Here, we investigated whether LRRK2 G2019S can increase the neurotoxicity induced by a mutant form of α-syn (A53T mutation) in DA neurons in vivo . Methods: We used a co-transduction approach with adeno-associated virus (AAV), AAV2/6 vectors encoding human α-syn A53T and the C-terminal portion of LRRK2 (ΔLRRK2), which contains the kinase domain, with either the G2019S mutation (ΔLRRK2 G2019S ) alone or the D1994A mutation (ΔLRRK2 G2019S/D1994A ), which inactivates the kinase activity of LRRK2. The AAVs were co-injected into the rat SNpc and histological evaluation was performed at 6- and 15-weeks post-injection (PI). Results: The majority of SNpc neurons co-expressed ΔLRRK2 and human α-syn A53T after transduction. ΔLRRK2 G2019S alone produced no cell loss at 15-weeks PI. Injection of AAV-α-syn A53T alone or mixed with a control AAV coding for GFP produced a significant loss of DA neurons. Co-injection of AAV-α-syn A53T with AAV-ΔLRRK2 G2019S instead of GFP slightly exacerbated that neuronal loss We also studied the inactive form, ΔLRRK2 G2019S/D1994A at 6 weeks PI. Injection of AAV-ΔLRRK2 G2019S mixed with AAV-α-syn A53T produced a neurotoxic effect that was stronger than that produced by the co-injection of AAV-DLRRK2 G2019S/D1994A and AAV-α-syn A53T . Conclusion: Thus, these results show that mutant LRRK2 may selectively facilitate α-syn toxicity in DA neurons through a cell-autonomous mechanism involving its kinase domain. However, considering that the effect of ΔLRRK2 G2019S upon human α-syn A53T is moderate in our paradigm where pathological proteins are overexpressed, the study supports the hypothesis that the interplay between LRRK2 and α-syn may also implicate non-cell-autonomous mechanisms such as those involved in neuroinflammation and spreading of α-syn aggregated species.

scholarly journals Fluorescence cytophotometric analysis of megakaryocytic ploidy in culture: studies of normal and thrombocytopenic mice

Blood ◽  
1984 ◽  
Vol 64 (6) ◽  
pp. 1193-1199 ◽  
Author(s):  
C Chatelain ◽  
SA Burstein
Keyword(s):  
Horse Serum ◽  
Fluorescence Emission ◽  
Inverse Correlation ◽  
Cell Loss ◽  
Pokeweed Mitogen ◽  
Rabbit Serum ◽  
Normal Rabbit Serum ◽  
Cytophotometric Analysis ◽  
And Control

Abstract A system for the accurate and rapid measurement of the ploidy of cultured megakaryocytes derived from megakaryocytic colony-forming cells (CFU-M) has been developed. Thirty thousand murine marrow cells per milliliter were cultured for varying time periods in agar in the presence of horse serum and pokeweed mitogen-stimulated spleen cell- conditioned medium (PWM-SCM). To ensure the inclusion of all the megakaryocytic cells in the analysis, entire agar discs were transferred onto glass slides and dried. Cells of the megakaryocytic lineage were identified by staining for acetylcholinesterase (AchE) for two hours. Subsequently, the nuclei of the cells were stained using 1.7 X 10(-5) mol/L chromomycin A3, a specific DNA-binding fluorochrome. Megakaryocytic colonies (greater than or equal to 2 AchE+ cells) were located under transmission light. The fluorescence emission of each cell of the colony was then measured by a photometer interfaced with a computer. The mean fluorescence emission of about 20 random granulocytes per slide was used as a 2N standard. There was no significant cell loss, quenching of fluorescence by AchE staining, or overlapping of colonies or cells. Approximately 100 megakaryocytes per hour could be analyzed. Modal ploidy of cultured megakaryocytes increased from 2N to 32N between days 3 and 6 in culture. Varying concentrations of PWM-SCM from 5% to 20% did not affect the ploidy distribution when examined at day 5. The heterogeneity of the ploidy of cells within colonies increased continuously with increasing cell numbers per colony. Clonal analyses of mean ploidy and ploidy heterogeneity did not show distinct types or classes of colonies; rather, the data show that megakaryocytic colonies are structured as a continuum. An inverse correlation was found between the number of cells constituting the colonies and their mean DNA content. To determine if short-term in vivo exposure of CFU-M to a thrombocytopenic environment could affect the ploidy of their progeny, mice were given rabbit antimouse-platelet serum while control animals were given normal rabbit serum. Twenty-four hours after injection, marrow derived from these animals was cultured. At day 5, the ploidy distributions and ploidy heterogeneity were identical in both treated and control groups. Thus, factor(s) that promote CFU-M proliferation do not affect megakaryocytic endoreduplication, while stimuli that acutely influence megakaryocytic ploidy in vivo do not determine the ultimate ploidy potential of megakaryocytes derived from a CFU-M.

scholarly journals Cryptococcal Phospholipase B1 Is Required for Intracellular Proliferation and Control of Titan Cell Morphology during Macrophage Infection

2015 ◽  
Vol 83 (4) ◽  
pp. 1296-1304 ◽  
Author(s):  
Robert J. Evans ◽  
Zhongming Li ◽  
William S. Hughes ◽  
Julianne T. Djordjevic ◽  
Kirsten Nielsen ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Virulence Factors ◽  
Fold Increase ◽  
Macrophage Infection ◽  
Content Type ◽  
The Central Nervous System ◽  
Opportunistic Fungal Pathogen ◽  
And Control

Cryptococcus neoformansis an opportunistic fungal pathogen and a leading cause of fungal-infection-related fatalities, especially in immunocompromised hosts. Several virulence factors are known to play a major role in the pathogenesis of cryptococcal infections, including the enzyme phospholipase B1 (Plb1). Compared to other well-studiedCryptococcus neoformansvirulence factors such as the polysaccharide capsule and melanin production, very little is known about the contribution of Plb1 to cryptococcal virulence. Phospholipase B1 is a phospholipid-modifying enzyme that has been implicated in multiple stages of cryptococcal pathogenesis, including initiation and persistence of pulmonary infection and dissemination to the central nervous system, but the underlying reason for these phenotypes remains unknown. Here we demonstrate that a Δplb1knockout strain ofC. neoformanshas a profound defect in intracellular growth within host macrophages. This defect is due to a combination of a 50% decrease in proliferation and a 2-fold increase in cryptococcal killing within the phagosome. In addition, we show for the first time that the Δplb1strain undergoes a morphological change duringin vitroandin vivointracellular infection, resulting in a subpopulation of very large titan cells, which may arise as a result of the attenuated mutant's inability to cope within the macrophage.

scholarly journals Cell Depletion Due to Diphtheria Toxin Fragment A after Cre-Mediated Recombination

2004 ◽  
Vol 24 (17) ◽  
pp. 7636-7642 ◽  
Author(s):  
Damian Brockschnieder ◽  
Corinna Lappe-Siefke ◽  
Sandra Goebbels ◽  
Michael R. Boesl ◽  
Klaus-Armin Nave ◽  
...  
Keyword(s):  
Diphtheria Toxin ◽  
Pyramidal Neurons ◽  
De Novo ◽  
Transgenic Animals ◽  
Cell Loss ◽  
Toxin Gene ◽  
Cell Type ◽  
Conditional Expression ◽  
The Central Nervous System

ABSTRACT Abnormal cell loss is the common cause of a large number of developmental and degenerative diseases. To model such diseases in transgenic animals, we have developed a line of mice that allows the efficient depletion of virtually any cell type in vivo following somatic Cre-mediated gene recombination. By introducing the diphtheria toxin fragment A (DT-A) gene as a conditional expression construct (floxed lacZ-DT-A) into the ubiquitously expressed ROSA26 locus, we produced a line of mice that would permit cell-specific activation of the toxin gene. Following Cre-mediated recombination under the control of cell-type-specific promoters, lacZ gene expression was efficiently replaced by de novo transcription of the Cre-recombined DT-A gene. We provide proof of this principle, initially for cells of the central nervous system (pyramidal neurons and oligodendrocytes), the immune system (B cells), and liver tissue (hepatocytes), that the conditional expression of DT-A is functional in vivo, resulting in the generation of novel degenerative disease models.

scholarly journals Neuroinflammation predicts disease progression in progressive supranuclear palsy

2020 ◽  
Author(s):  
Maura Malpetti ◽  
Luca Passamonti ◽  
P. Simon Jones ◽  
Duncan Street ◽  
Timothy Rittman ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Disease Progression ◽  
Brain Atrophy ◽  
Rating Scale ◽  
Neuronal Loss ◽  
Principal Component ◽  
Rate Of Change ◽  
Tau Pathology ◽  
Clinical Progression

Objective: In addition to tau pathology and neuronal loss, neuroinflammation occurs in progressive supranuclear palsy (PSP). We test the hypotheses that baseline in vivo assessments of regional neuroinflammation ([11C]PK11195 PET), tau pathology ([18F]AV-1451 PET), and atrophy (structural MRI) predict disease progression. Methods: Seventeen patients with PSP-Richardson′s syndrome underwent a baseline multi-modal imaging assessment. Disease severity was measured at baseline and serially up to 4 years with the PSP-rating-scale (average interval 5 months). Regional grey-matter volumes and PET ligand binding potentials were summarised by three Principal Component Analyses (PCAs). A linear mixed effects model was applied to the longitudinal PSP-rating-scale scores. Single-modality imaging predictors were regressed against the individuals′ estimated rate of progression to identify the prognostic value of baseline imaging markers. Results: The PCA factors reflecting neuroinflammation and tau burden in the brainstem and cerebellum correlated with the subsequent annual rate of change in the PSP-rating-scale. PCA-derived PET markers of neuroinflammation and tau pathology correlated with brain atrophy in the same regions. However, MRI markers of brain atrophy alone did not predict clinical progression. Conclusions: Molecular imaging with PET can predict clinical progression in PSP. These data encourage the evaluation of immunomodulatory approaches to disease-modifying therapies in PSP, and the potential for PET to stratify patients for early phase clinical trials.

scholarly journals The Air We Breathe: Air Pollution as a Prevalent Proinflammatory Stimulus Contributing to Neurodegeneration

2021 ◽  
Vol 15 ◽  
Author(s):  
Monika Jankowska-Kieltyka ◽  
Adam Roman ◽  
Irena Nalepa
Keyword(s):  
Air Pollution ◽  
Neurodegenerative Disease ◽  
Air Pollutants ◽  
Disease Onset ◽  
Circulatory System ◽  
Epidemiological Studies ◽  
The Body ◽  
The Central Nervous System

Air pollution is regarded as an important risk factor for many diseases that affect a large proportion of the human population. To date, accumulating reports have noted that particulate matter (PM) is closely associated with the course of cardiopulmonary disorders. As the incidence of Alzheimer’s disease (AD), Parkinson’s disease (PD), and autoimmune disorders have risen and as the world’s population is aging, there is an increasing interest in environmental health hazards, mainly air pollution, which has been slightly overlooked as one of many plausible detrimental stimuli contributing to neurodegenerative disease onset and progression. Epidemiological studies have indicated a noticeable association between exposure to PM and neurotoxicity, which has been gradually confirmed by in vivo and in vitro studies. After entering the body directly through the olfactory epithelium or indirectly by passing through the respiratory system into the circulatory system, air pollutants are subsequently able to reach the brain. Among the potential mechanisms underlying particle-induced detrimental effects in the periphery and the central nervous system (CNS), increased oxidative stress, inflammation, mitochondrial dysfunction, microglial activation, disturbance of protein homeostasis, and ultimately, neuronal death are often postulated and concomitantly coincide with the main pathomechanisms of neurodegenerative processes. Other complementary mechanisms by which PM could mediate neurotoxicity and contribute to neurodegeneration remain unconfirmed. Furthermore, the question of how strong and proven air pollutants are as substantial adverse factors for neurodegenerative disease etiologies remains unsolved. This review highlights research advances regarding the issue of PM with an emphasis on neurodegeneration markers, symptoms, and mechanisms by which air pollutants could mediate damage in the CNS. Poor air quality and insufficient knowledge regarding its toxicity justify conducting scientific investigations to understand the biological impact of PM in the context of various types of neurodegeneration.

scholarly journals Impaired ureagenesis due to arginine-insensitive N-acetylglutamate synthase

2018 ◽  
Author(s):  
Parthasarathy Sonaimuthu ◽  
Emilee Senkevitch ◽  
Nantaporn Haskins ◽  
Prech Uapinyoying ◽  
Markey McNutt ◽  
...  
Keyword(s):  
Urea Cycle ◽  
Ammonia Concentration ◽  
Ammonia Toxicity ◽  
Wild Type ◽  
Adeno Associated Virus ◽  
The Central Nervous System ◽  
Acetylglutamate Synthase ◽  
And Control ◽  
Carbamylphosphate Synthetase

AbstractThe urea cycle protects the central nervous system from ammonia toxicity by converting ammonia to non-toxic urea. N-acetylglutamate synthase (NAGS) is an enzyme that catalyzes the formation of N-acetylglutamate (NAG), an allosteric activator of carbamylphosphate synthetase 1 (CPS1), the rate limiting enzyme of the urea cycle. Enzymatic activity of mammalian NAGS doubles in the presence of L-arginine but the physiological significance of NAGS activation by L-arginine is unknown. Previously, we have described the creation of a NAGS knockout (Nags−/−) mouse, which develops hyperammonemia without N-carbamylglutamate and L-citrulline supplementation (NCG+Cit). In order to investigate the effect of L-arginine on ureagenesis in vivo, we used adeno associated virus (AAV) mediated gene transfer to deliver either wild-type or E354A mutant mouse NAGS (mNAGS), which is not activated by L-arginine, to Nags−/− mice. The ability of the E354A mNAGS mutant protein to rescue Nags−/− mice was determined by measuring their activity on the voluntary wheel following NCG+Cit withdrawal. The Nags−/− mice that received E354A mNAGS remained apparently healthy and active but had elevated plasma ammonia concentration despite similar expression levels of the E354A mNAGS and control wild-type NAGS proteins. The corresponding mutation in human NAGS (NP 694551.1:p.E360D) that abolishes binding and activation by L-arginine was also identified in a patient with hyperammonemia due to NAGS deficiency. Taken together, our results suggest that L-arginine binding to the NAGS enzyme is essential for normal ureagenesis.

scholarly journals Parkinsonism Associated with Pathological 123I-FP-CIT SPECT (DaTSCAN) Results as the Initial Manifestation of Sporadic Creutzfeldt-Jakob Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-3
Author(s):  
Sira Carrasco García de León ◽  
Juan Pablo Cabello ◽  
Ramón Ortiz ◽  
Julia Vaamonde
Keyword(s):  
Central Nervous System ◽  
Disease Onset ◽  
Initial Manifestation ◽  
Jakob Disease ◽  
The Central Nervous System ◽  
Clinical Variants ◽  
Scjd Patient ◽  
Spongiform Degeneration ◽  
Symptoms And Signs

Sporadic Creutzfeldt-Jakob disease (sCJD) is a type of progressive, subacute encephalopathy associated with spongiform degeneration of the central nervous system. sCJD includes a broad and heterogeneous spectrum of clinical variants, but extrapyramidal symptoms and signs at disease onset were rarely reported. We describe a case of unilateral parkinsonism associated with pathological 123I-ioflupane SPECT (DaTSCAN) results as the initial manifestation of M129V subtype sCJD patient. To the best of our knowledge, only 2 cases of Creutzfeldt-Jakob disease demonstrating nigrostriatal dopaminergic deficits in vivo using DaTSCAN have been published in the literature.

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