RESUMEN
A hallmark of Parkinson's disease is the specific degeneration of dopaminergic neurons in the substantia nigra pars compacta. Interestingly, not all of these neurons are affected to the same extent. Studies revealed that neurons located more ventrally within the substantia nigra pars compacta have a higher prevalence to degenerate than those located in the dorsal tier. The underlying reasons for this selective neuronal vulnerability are still unknown. The aim of the present study was to gain a better understanding of molecular differences between these two neuronal subpopulations that may explain the selective neuronal vulnerability within the human substantia nigra. For this purpose, the neurons from the ventral as well as dorsal tier of the substantia nigra were specifically isolated out of neuropathologically unremarkable human substantia nigra sections with laser microdissection. Following, their proteome was analyzed by data independent acquisition mass spectrometry. The samples were analysed donor-specifically and not pooled for this purpose. A total of 5,391 proteins were identified in the substantia nigra. Of these, 2,453 proteins could be quantified in 100% of the dorsal tier samples. 1,629 could be quantified in 100% of the ventral tier samples. Nine proteins were differentially regulated with a log2 value ≥0.5 and a Qvalue ≤0.05. Of these 7 were higher abundant in the dorsal tier and 2 higher in the ventral tier. These proteins are associated with the cytoskeleton, neuronal plasticity, or calcium homeostasis. With these findings a deeper understanding can be gained of the selective neuronal vulnerability within the substantia nigra and of protective mechanisms against neurodegeneration in specific neuronal subpopulations.
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Sustancia Negra , Humanos , Sustancia Negra/metabolismo , Sustancia Negra/patología , Masculino , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Anciano , Femenino , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Persona de Mediana Edad , Anciano de 80 o más Años , Proteómica/métodos , Neuronas/metabolismo , Neuronas/patología , Proteoma/metabolismo , Proteoma/análisisRESUMEN
Data on the participation of microbiota in the development of Parkinson's disease allow us to discuss the ability of bacterial preparations to influence the processes leading to neurodegeneration. We studied the effect of oral administration of Limosilactobacillus fermentum U-21 lyophilisate on a model of Parkinson's disease in rats induced by combined intranigral injection of LPS and systemic administration of paraquat. The toxins significantly increased the number of missteps in the "narrowing beam walking" test, but a tendency to a decrease in this parameter was shown after treatment with U-21. It should be noted that U-21 did not reduce the neuronal death in the substantia nigra, but mitigated the inflammatory glial response, decreased the accumulation of phosphorylated α-synuclein and complement protein C3. Our study demonstrated the efficiency of the combined model of parkinsonism and reduction of proinflammatory changes under the influence of pharmabiotic without changes in the nigral neuronal death and motor deficits.
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Modelos Animales de Enfermedad , Lipopolisacáridos , Sustancia Negra , alfa-Sinucleína , Animales , Ratas , alfa-Sinucleína/metabolismo , Masculino , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Sustancia Negra/patología , Lipopolisacáridos/farmacología , Lipopolisacáridos/toxicidad , Paraquat , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Ratas Wistar , Complemento C3/metabolismo , Enfermedades Neuroinflamatorias/patología , Enfermedades Neuroinflamatorias/tratamiento farmacológicoRESUMEN
Parkinson's disease (PD), which is the second most common neurodegenerative disorder, is characterized by progressive movement impairment and loss of midbrain dopaminergic neurons in the substantia nigra. Although mutations in TMEM230 are linked to familial PD, the pathogenic mechanism underlying TMEM230-associated PD remains to be elucidated. To explore the effect of TMEM230 depletion in vivo, we created TMEM230 knockout rats using CRISPR-Cas9 technology. TMEM230 knockout rats did not exhibit any core features of PD, including impaired motor function, loss of dopaminergic neurons in the substantia nigra, or altered expression of proteins related to autophagy, the Rab family, or vesicular trafficking. In addition, no glial reactions were observed in TMEM230 knockout rats. These results indicate that depletion of TMEM230 may not lead to dopaminergic neuron degeneration in rats, further supporting that PD-associated TMEM230 mutations lead to dopaminergic neuron death by gain-of-toxic function.
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Neuronas Dopaminérgicas , Animales , Neuronas Dopaminérgicas/patología , Neuronas Dopaminérgicas/metabolismo , Ratas , Proteínas de la Membrana/genética , Sustancia Negra/patología , Sustancia Negra/metabolismo , Técnicas de Inactivación de Genes/métodos , Masculino , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Ratas Sprague-DawleyRESUMEN
The effect of the modulators of the mitochondrial ATP-dependent potassium channel (mitoKATP) on the structural and biochemical alterations in the substantia nigra and brain tissues was studied in a rat model of Parkinson's disease induced by rotenone. It was found that, in experimental parkinsonism accompanied by characteristic motor deficits, both neurons and the myelin sheath of nerve fibers in the substantia nigra were affected. Changes in energy and ion exchange in brain mitochondria were also revealed. The nucleoside uridine, which is a source for the synthesis of the mitoKATP channel opener uridine diphosphate, was able to dose-dependently decrease behavioral disorders and prevent the death of animals, which occurred for about 50% of animals in the model. Uridine prevented disturbances in redox, energy, and ion exchanges in brain mitochondria, and eliminated alterations in their structure and the myelin sheath in the substantia nigra. Cytochemical examination showed that uridine restored the indicators of oxidative phosphorylation and glycolysis in peripheral blood lymphocytes. The specific blocker of the mitoKATP channel, 5-hydroxydecanoate, eliminated the positive effects of uridine, suggesting that this channel is involved in neuroprotection. Taken together, these findings indicate the promise of using the natural metabolite uridine as a new drug to prevent and, possibly, stop the progression of Parkinson's disease.
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Mitocondrias , Canales de Potasio , Rotenona , Uridina , Animales , Uridina/farmacología , Uridina/metabolismo , Ratas , Canales de Potasio/metabolismo , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Masculino , Modelos Animales de Enfermedad , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/patología , Sustancia Negra/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Fármacos Neuroprotectores/farmacología , Fosforilación Oxidativa/efectos de los fármacos , Ratas Wistar , Ácidos Decanoicos/farmacología , Hidroxiácidos/farmacologíaRESUMEN
AIMS: Astrocytic tau pathology is a major feature of tauopathies and ageing-related tau astrogliopathy (ARTAG). The substantia nigra (SN) is one of the important degenerative areas in tauopathies with parkinsonism. Nigral tau pathology is usually reported as neuronal predominant with less prominent astrocytic involvement. We aimed to identify cases with prominent astrocytic tau pathology in the SN. METHODS: We use the term nigral tau-astrogliopathy (NITAG) to describe cases showing an unusually high density of ARTAG with less neuronal tau pathology in the SN. We collected clinical information and studied the distribution of tau pathology, morphological features and immunostaining profiles in three cases. RESULTS: Three cases, all males with parkinsonism, were identified with the following clinicopathological diagnoses: (i) atypical parkinsonism with tau pathology reminiscent to that in postencephalitic parkinsonism (69-year-old); (ii) multiple system atrophy (73-year-old); (iii) traumatic encephalopathy syndrome/chronic traumatic encephalopathy (84-year-old). Double-labelling immunofluorescence confirmed co-localization of GFAP and phosphorylated tau in affected astrocytes. Staining profiles of NITAG revealed immunopositivity for various phosphorylated tau antibodies. Some astrocytic tau lesions were also seen in other brainstem regions and cerebral grey matter. CONCLUSIONS: We propose NITAG is a rare neuropathological feature, and not a distinct disease entity, in the frame of multiple system ARTAG, represented by abundant tau-positive astrocytes in various brain regions but having the highest density in the SN. The concept of NITAG allows the stratification of cases with various background pathologies to understand its relevance and contribution to neuronal dysfunction.
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Envejecimiento , Astrocitos , Sustancia Negra , Tauopatías , Proteínas tau , Humanos , Masculino , Sustancia Negra/patología , Sustancia Negra/metabolismo , Anciano , Astrocitos/patología , Astrocitos/metabolismo , Tauopatías/patología , Tauopatías/metabolismo , Anciano de 80 o más Años , Envejecimiento/patología , Proteínas tau/metabolismo , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/metabolismoRESUMEN
The pursuit of drugs and methods to safeguard dopaminergic neurons holds paramount importance in Parkinson's disease (PD) research. Benfotiamine (BFT) has demonstrated neuroprotective properties, yet its precise mechanisms in PD remain elusive. This study investigated BFT's potential protective effects against dopamine neuron damage in a PD animal model and the underlying mechanisms. The PD mouse model was induced by 5 consecutive MPTP injections, followed by BFT intervention for 28 days. Motor deficits were assessed via pole test, hang test, gait analysis, and open field test, while dopaminergic neuron damage was evaluated through Immunofluorescence, Nissl staining, and Western blot analysis of Tyrosine Hydroxylase (TH) in the substantia nigra and striatum. High Performance Liquid Chromatography quantified dopamine (DA) levels and its metabolites. Genetic pathways were explored using RNA-seq and bioinformatics analysis on substantia nigra tissues, confirmed by qPCR. Activation of the Nrf2 pathway was examined through nuclear translocation and expression of downstream antioxidant enzymes HO-1, GCLM, and NQO1 at mRNA and protein levels. Additionally, measurements of MDA content, GSH activity, and SOD activity were taken in the substantia nigra and striatum. BFT administration improved motor function and protected against dopaminergic neuron degeneration in MPTP mice, with partial recovery in TH expression and DA levels. RNA-seq analysis revealed distinct effects of BFT and the NLRP3 inhibitor MCC950 on Parkinson-related pathways and genes. Control of Nrf2 proved crucial for BFT, as it facilitated Nrf2 movement to the nucleus, upregulating antioxidant genes and enzymes while mitigating oxidative damage. This study elucidates BFT's neuroprotective effects in a PD mouse model via Nrf2-mediated antioxidant mechanisms and gene expression modulation, underscoring its potential as a therapeutic agent for PD.
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Modelos Animales de Enfermedad , Factor 2 Relacionado con NF-E2 , Fármacos Neuroprotectores , Transducción de Señal , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal/efectos de los fármacos , Ratones , Masculino , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Ratones Endogámicos C57BL , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Dopamina/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Sustancia Negra/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Estrés Oxidativo/efectos de los fármacos , Tiamina/análogos & derivadosRESUMEN
Aggregation of the protein α-Synuclein (αSyn) is a hallmark of Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple systems atrophy, and alleviating the extent of αSyn pathology is an attractive strategy against neurodegeneration. The engineered binding protein ß-wrapin AS69 binds monomeric αSyn. AS69 reduces primary and secondary nucleation as well as fibril elongation in vitro. It also mitigates aSyn pathology in a mouse model based on intrastriatal injection of aSyn pre-formed fibrils (PFFs). Since the PFF-based model does not represent all aspects of PD, we tested here whether AS69 can reduce neurodegeneration resulting from αSyn overexpression. Human A53T-αSyn was overexpressed in the mouse Substantia nigra (SN) by using recombinant adeno-associated viral vector (rAAV). AS69 was also expressed by rAAV transduction. Behavioral tests and immunofluorescence staining were used as outcomes. Transduction with rAAV-αSyn resulted in αSyn pathology as reported by phospho-αSyn staining and caused degeneration of dopaminergic neurons in the SN. The co-expression of rAAV-AS69 did not reduce αSyn pathology or the degeneration of dopaminergic neurons. We conclude that αSyn monomer binding by rAAV-AS69 was insufficient to protect from aSyn pathology resulting from αSyn overexpression.
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Modelos Animales de Enfermedad , Sustancia Negra , alfa-Sinucleína , Animales , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Ratones , Humanos , Sustancia Negra/metabolismo , Sustancia Negra/patología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Dependovirus/genética , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Masculino , Ratones Endogámicos C57BLRESUMEN
Parkinson's disease (PD) is a debilitating neurodegenerative disease affecting millions of individuals worldwide. Hallmark features of PD pathology are the formation of Lewy bodies in neuromelanin-containing dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNpc), and the subsequent irreversible death of these neurons. Although genetic risk factors have been identified, around 90â¯% of PD cases are sporadic and likely caused by environmental exposures and gene-environment interaction. Mechanistic studies have identified a variety of chemical PD risk factors. PD neuropathology occurs throughout the brain and peripheral nervous system, but it is the loss of DAergic neurons in the SNpc that produce many of the cardinal motor symptoms. Toxicology studies have found specifically the DAergic neuron population of the SNpc exhibit heightened sensitivity to highly variable chemical insults (both in terms of chemical structure and mechanism of neurotoxic action). Thus, it has become clear that the inherent neurobiology of nigral DAergic neurons likely underlies much of this neurotoxic response to broad insults. This review focuses on inherent neurobiology of nigral DAergic neurons and how such neurobiology impacts the primary mechanism of neurotoxicity. While interactions with a variety of other cell types are important in disease pathogenesis, understanding how inherent DAergic biology contributes to selective sensitivity and primary mechanisms of neurotoxicity is critical to advancing the field. Specifically, key biological features of DAergic neurons that increase neurotoxicant susceptibility.
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Neuronas Dopaminérgicas , Humanos , Animales , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Neuronas Dopaminérgicas/metabolismo , Dopamina/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Sustancia Negra/metabolismoRESUMEN
Parkinson's disease (PD) is the most common neurodegenerative movement disorder worldwide. Current treatments for PD largely center around dopamine replacement therapies and fail to prevent the progression of pathology, underscoring the need for neuroprotective interventions. Approaches that target neuroinflammation, which occurs prior to dopaminergic neuron (DAn) loss in the substantia nigra (SN), represent a promising therapeutic strategy. The glucocorticoid receptor (GR) has been implicated in the neuropathology of PD and modulates numerous neuroinflammatory signaling pathways in the brain. Therefore, we investigated the neuroprotective effects of the novel GR modulator, PT150, in the rotenone mouse model of PD, postulating that inhibition of glial inflammation would protect DAn and reduce accumulation of neurotoxic misfolded âº-synuclein protein. C57Bl/6 mice were exposed to 2.5â¯mg/kg/day rotenone by intraperitoneal injection for 14 days. Upon completion of rotenone dosing, mice were orally treated at day 15 with 30â¯mg/kg/day or 100â¯mg/kg/day PT150 in the 14-day post-lesioning incubation period, during which the majority of DAn loss and α-synuclein (α-syn) accumulation occurs. Our results indicate that treatment with PT150 reduced both loss of DAn and microgliosis in the nigrostriatal pathway. Although morphologic features of astrogliosis were not attenuated, PT150 treatment promoted potentially neuroprotective activity in these cells, including increased phagocytosis of hyperphosphorylated α-syn. Ultimately, PT150 treatment reduced the loss of DAn cell bodies in the SN, but not the striatum, and prohibited intra-neuronal accumulation of α-syn. Together, these data indicate that PT150 effectively reduced SN pathology in the rotenone mouse model of PD.
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Neuronas Dopaminérgicas , Ratones Endogámicos C57BL , Fármacos Neuroprotectores , Receptores de Glucocorticoides , Rotenona , alfa-Sinucleína , Animales , Rotenona/toxicidad , Fármacos Neuroprotectores/farmacología , Ratones , Masculino , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Neuronas Dopaminérgicas/metabolismo , Receptores de Glucocorticoides/metabolismo , alfa-Sinucleína/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Sustancia Negra/metabolismo , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Modelos Animales de Enfermedad , FenantrenosRESUMEN
Agyrophilic grains (AGs) are age-related limbic-predominant lesions in which four-repeat tau is selectively accumulated. Because previous methodologically heterogeneous studies have demonstrated inconsistent findings on the relationship between AGs and dementia, whether AGs affect cognitive function remains unclear. To address this question, we first comprehensively evaluated the distribution and quantity of Gallyas-positive AGs and the severity of neuronal loss in the limbic, neocortical, and subcortical regions in 30 cases of pure argyrophilic grain disease (pAGD) in Braak stages I-IV and without other degenerative diseases, and 34 control cases that had only neurofibrillary tangles with Braak stages I-IV and no or minimal Aß deposits. Then, we examined whether AGs have independent effects on neuronal loss and dementia by employing multivariate ordered logistic regression and binomial logistic regression. Of 30 pAGD cases, three were classified in diffuse form pAGD, which had evident neuronal loss not only in the limbic region but also in the neocortex and subcortical nuclei. In all 30 pAGD cases, neuronal loss developed first in the amygdala, followed by temporo-frontal cortex, hippocampal CA1, substantia nigra, and finally, the striatum and globus pallidus with the progression of Saito AG stage. In multivariate analyses of 30 pAGD and 34 control cases, the Saito AG stage affected neuronal loss in the amygdala, hippocampal CA1, temporo-frontal cortex, striatum, globus pallidus, and substantia nigra independent of the age, Braak stage, and limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) stage. In multivariate analyses of 23 pAGD and 28 control cases that lacked two or more lacunae and/or one or more large infarctions, 100 or more AGs per × 400 visual field in the amygdala (OR 10.02, 95% CI 1.12-89.43) and hippocampal CA1 (OR 12.22, 95% CI 1.70-87.81), and the presence of AGs in the inferior temporal cortex (OR 8.18, 95% CI 1.03-65.13) affected dementia independent of age, moderate Braak stages (III-IV), and LATE-NC. Given these findings, the high density of limbic AGs and the increase of AGs in the inferior temporal gyrus may contribute to the occurrence of dementia through neuronal loss, at least in cases in a low to moderate Braak stage.
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Demencia , Neocórtex , Humanos , Masculino , Femenino , Anciano , Anciano de 80 o más Años , Demencia/patología , Neocórtex/patología , Sistema Límbico/patología , Persona de Mediana Edad , Ovillos Neurofibrilares/patología , Sustancia Negra/patología , Globo Pálido/patología , Enfermedades Neurodegenerativas/patologíaRESUMEN
INTRODUCTION: The substantia nigra pars compacta (SNc) is the key pathologic locus in neurodegenerative parkinsonian disorders. Recently, in vivo susceptibility MRI metrics were associated with postmortem glial cell density and tau burden in the SNc of parkinsonism subjects. This study investigated the red nucleus (RN), another iron-rich region adjacent to the SNc and a potential site of higher functionality in parkinsonisms. METHODS: In vivo MRI and postmortem data were obtained from 34 parkinsonism subjects and 3 controls. Neuron density, glial cell density, and percentages of area occupied by α-synuclein and tau were quantified using digitized midbrain slides. R2* and quantitative susceptibility mapping (QSM) metrics in the RN and SNc were derived from multi-gradient echo images. Histopathology data were compared between the RN and SNc using paired t-tests. MRI-histology associations were analyzed using partial Pearson correlations. RESULTS: The RN had greater neuron (t23 = 3.169, P = 0.004) and glial cell densities (t23 = 2.407, P = 0.025) than the SNc, whereas the SNc had greater α-synuclein (t28 = 4.614, P < 0.0001) and tau burden (t24 = 4.513, P = 0.0001). In both the RN (R2*: r = 0.47, P = 0.043; QSM: r = 0.52, P = 0.024) and SNc (R2*: r = 0.57, P = 0.01; QSM: r = 0.58, P = 0.009), MRI values were associated with glial cell density but not neuron density or α-synuclein (Ps > 0.092). QSM associated with tau burden (r = 0.49, P = 0.038) in the SNc, but not the RN. CONCLUSIONS: The RN is resilient to parkinsonian-related pathological processes compared to the SNc, and susceptibility MRI captured glial cell density in both regions. These findings help to further our understanding of the underlying pathophysiological processes in parkinsonisms.
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Imagen por Resonancia Magnética , Trastornos Parkinsonianos , Porción Compacta de la Sustancia Negra , Núcleo Rojo , Sustancia Negra , Humanos , Núcleo Rojo/diagnóstico por imagen , Núcleo Rojo/patología , Núcleo Rojo/metabolismo , Masculino , Anciano , Femenino , Porción Compacta de la Sustancia Negra/diagnóstico por imagen , Porción Compacta de la Sustancia Negra/patología , Porción Compacta de la Sustancia Negra/metabolismo , Anciano de 80 o más Años , Persona de Mediana Edad , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/metabolismo , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/patología , Sustancia Negra/metabolismo , Proteínas tau/metabolismo , Neuroglía/patología , Neuroglía/metabolismo , alfa-Sinucleína/metabolismo , Neuronas/patología , Neuronas/metabolismoRESUMEN
Parkinson's disease (PD) is a chronic neurodegenerative disease with unclear pathogenesis that involves neuroinflammation and intestinal microbial dysbiosis. Intercellular adhesion molecule-1 (ICAM-1), an inflammatory marker, participates in neuroinflammation during dopaminergic neuronal damage. However, the explicit mechanisms of action of ICAM-1 in PD have not been elucidated. We established a subacute PD mouse model by the intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and observed motor symptoms and gastrointestinal dysfunction in mice. Immunofluorescence was used to examine the survival of dopaminergic neurons, expression of microglial and astrocyte markers, and intestinal tight junction-associated proteins. Then, we use 16â¯S rRNA sequencing to identify alterations in the microbiota. Our findings revealed that ICAM-1-specific antibody (Ab) treatment relieved behavioural defects, gastrointestinal dysfunction, and dopaminergic neuronal death in MPTP-induced PD mice. Further mechanistic investigations indicated that ICAM-1Ab might suppress neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra and relieving colon barrier impairment and intestinal inflammation. Furthermore, 16â¯S rRNA sequencing revealed that the relative abundances of bacterial Firmicutes, Clostridia, and Lachnospiraceae were elevated in the PD mice. However, ICAM-1Ab treatment ameliorated the MPTP-induced disorders in the intestinal microbiota. Collectively, we concluded that the suppressing ICAM-1 might lead to the a significant decrease of inflammation and restore the gut microbial community, thus ameliorating the damage of DA neurons.
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Neuronas Dopaminérgicas , Molécula 1 de Adhesión Intercelular , Ratones Endogámicos C57BL , Animales , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Neuronas Dopaminérgicas/efectos de los fármacos , Molécula 1 de Adhesión Intercelular/metabolismo , Ratones , Masculino , Modelos Animales de Enfermedad , Enfermedades Neuroinflamatorias/metabolismo , Microbioma Gastrointestinal/fisiología , Microbioma Gastrointestinal/efectos de los fármacos , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Inflamación/metabolismo , Sustancia Negra/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Microglía/metabolismo , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Trastornos Parkinsonianos/metabolismo , Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/patologíaRESUMEN
For a special issue, we review studies on the pathogenesis of nigral cell death and the treatment of sporadic Parkinson's disease (sPD) over the past few decades, with a focus on the studies performed by Prof. Mizuno and our group. Prof. Mizuno proposed the initial concept that mitochondrial function may be impaired in sPD. When working at Jichi Medical School, he found a decrease in complex I of the mitochondrial electron transfer complex in the substantia nigra of patients with Parkinson's disease (PD) and MPTP models. After moving to Juntendo University as a professor and chairman, he continued to study the mechanisms of cell death in the substantia nigra of patients with sPD. Under his supervision, I studied the relationships between PD and apoptosis, PD and iron involvement, mitochondrial dysfunction and apoptosis, and PD and neuroinflammation. Moving to Kitasato University, we focused on PD and the cytotoxicity of alpha synuclein (αSyn) as well as brain neuropathology. Eventually, I moved to Osaka University, where I continued working on PD and αSyn projects to promote therapeutic research. In this paper, we present the details of these studies in the following order: past, present, and future.
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Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/metabolismo , Animales , Sustancia Negra/patología , Sustancia Negra/metabolismo , alfa-Sinucleína/metabolismoRESUMEN
Endosomal acid base balance functions as a master orchestrator within the cell, engaging with many cellular pathways to maintain homeostasis. Mutations in the endosomal pH regulator Na+/H+ exchanger NHE6 may disrupt this delicate balancing act and cause monogenic Parkinsonism. Here, gene expression studies in post-mortem substantia nigra of Parkinson's disease (PD) patients and normal controls were performed to investigate whether NHE6 represents a pathophysiological link between monogenic and sporadic PD. The substantia nigra in PD displayed down-regulation of NHE6, coincident with a loss of expression of several SNARE signalling pathway members, suggesting impaired membrane fusion and vesicle-recycling. Increased abundance of related NHE9 was also identified in the parkinsonian nigra that could reflect compensatory changes or be a consequence of neuronal dysfunction. The current model suggests the possibility that neurons expressing low levels of NHE6 are more susceptible to injury in PD, potentially directly contributing to the loss of nigral dopaminergic neurons and the genesis of the disease. These results have important implications for disease-modifying therapies as they suggest that endosomal pH correctors, including epigenetic modifiers that regulate NHE6 expression, may be beneficial for PD. Thus, aberrant endosomal acidification in the nigrostriatal pathway is a possible unifying pathomechanism in both monogenic and sporadic PD, with implications for understanding and treating this disorder. Replication of these observations in the post-mortem brains of Alzheimer's disease and frontotemporal dementia patients supports a model of conserved mechanisms underlying injury and death of neurons.
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Endosomas , Enfermedad de Parkinson , Intercambiadores de Sodio-Hidrógeno , Sustancia Negra , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Humanos , Sustancia Negra/metabolismo , Sustancia Negra/patología , Intercambiadores de Sodio-Hidrógeno/genética , Intercambiadores de Sodio-Hidrógeno/metabolismo , Masculino , Endosomas/metabolismo , Femenino , Anciano , Concentración de Iones de Hidrógeno , Persona de Mediana Edad , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Anciano de 80 o más Años , Estudios de Casos y ControlesRESUMEN
BACKGROUND: Parkinson's disease (PD) manifests as a wide variety of clinical phenotypes and its progression varies greatly. However, the factors associated with different disease progression remain largely unknown. METHODS: In this retrospective cohort study, we enrolled 113 patients who underwent 18F-FP-CIT PET scan twice. Given the negative exponential progression pattern of dopamine loss in PD, we applied the natural logarithm to the specific binding ratio (SBR) of two consecutive 18F-FP-CIT PET scans and conducted linear mixed model to calculate individual slope to define the progression rate of nigrostriatal degeneration. We investigated the clinical and dopamine transporter (DAT) availability patterns associated with the progression rate of dopamine depletion in each striatal sub-region. RESULTS: More symmetric parkinsonism, the presence of dyslipidemia, lower K-MMSE total score, and lower anteroposterior gradient of the mean putaminal SBR were associated with faster progression rate of dopamine depletion in the caudate nucleus. More symmetric parkinsonism and lower anteroposterior gradient of the mean putaminal SBR were associated with faster depletion of dopamine in the anterior putamen. Older age at onset, more symmetric parkinsonism, the presence of dyslipidemia, and lower anteroposterior gradient of the mean putaminal SBR were associated with faster progression rate of dopamine depletion in the posterior putamen. Lower striatal mean SBR predicted the development of LID, while lower mean SBR in the caudate nuclei predicted the development of dementia. DISCUSSION: Our results suggest that the evaluation of baseline clinical features and patterns of DAT availability can predict the progression of PD and its prognosis.
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Cuerpo Estriado , Progresión de la Enfermedad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Enfermedad de Parkinson , Tomografía de Emisión de Positrones , Humanos , Masculino , Femenino , Anciano , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/complicaciones , Estudios Retrospectivos , Persona de Mediana Edad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Tropanos , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/metabolismo , Sustancia Negra/patologíaRESUMEN
Background: Parkinson's disease (PD) is characterized by alpha-synuclein (α-Syn) pathology, neurodegeneration and neuroinflammation. Human leukocyte antigen (HLA) variants associated with PD and α-Syn specific CD4+ T lymphocytes in PD patients highlight the importance of antigen presentation in PD etiology. The class II transactivator (CIITA) regulates major histocompatibility complex class II (MHCII) expression. Reduced Ciita levels significantly increase α-Syn pathology, nigrostriatal neurodegeneration and behavioral deficits in α-Syn-induced rat PD models. Objective: Characterize immune profiles associated with enhanced PD-like pathology observed in rats expressing lower Ciita levels (DA.VRA4) compared to the background strain (DA). Methods: To model PD, we combined rAAV-mediated α-Syn overexpression in the substantia nigra with striatal injection of α-Syn preformed fibrils. Immune profiles in brain and blood were analyzed by flow cytometry and multiplexed ELISA in naïve rats, 4- and 8 weeks post rAAV injection. Results: Flow cytometry showed Ciita-dependent regulation of MHCII on microglia, brain macrophages and circulating myeloid cells. The MHCII-dependent microglial response was highest at 4 weeks post rAAV injection, whereas the MHCII levels in circulating myeloid cells was highest at 8 weeks. There was no major infiltration of macrophages or T lymphocytes into the CNS in response to α-Syn and only subtle Ciita- and/or α-Syn-dependent changes in the T lymphocyte compartment. Lower Ciita levels were consistently associated with higher TNF levels in serum. Conclusions: Ciita regulates susceptibility to PD-like pathology through minor but detectable changes in resident and peripheral immune cells and TNF levels, indicating that mild immunomodulatory therapies could have therapeutic effects in PD.
Parkinson's disease is characterized by loss of nerve cells. There is also abnormal aggregation of a protein called alpha-synuclein and an ongoing inflammatory response. Findings that immune cells in the blood of individuals with Parkinson's disease react against the alpha-synuclein protein and that genes important for the immune system affect the risk of developing Parkinson's disease indicate that immune responses are important in Parkinson's disease. We have previously found that a low expression of certain immune molecules worsens disease progression in a rat model of Parkinson's disease. The aim of this study was to identify changes in the immune system in rats that are associated with disease severity, to identify mechanisms that could be targeted to treat Parkinson's disease. To model Parkinson's disease, we injected a modified virus to produce large amounts of alpha-synuclein combined with an injection of aggregated alpha-synuclein proteins in the rat brain. The model mimics several features of Parkinson's disease including nerve cell death, problems with movement, accumulation of alpha-synuclein in the brain, and an immune response. We observed that the immune system in the brain and blood responded to the model but that differences were small compared to controls. Our results suggest that small changes in the immune system can have a large effect on disease progression and that therapies targeting the immune system are worth exploring to find better treatment for Parkinson's disease.
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Modelos Animales de Enfermedad , Enfermedad de Parkinson , Transactivadores , alfa-Sinucleína , Animales , alfa-Sinucleína/metabolismo , Ratas , Transactivadores/genética , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/terapia , Proteínas Nucleares/metabolismo , Sustancia Negra/patología , Sustancia Negra/metabolismo , Sustancia Negra/inmunología , Masculino , Dependovirus , Microglía/inmunología , Microglía/metabolismo , Microglía/patologíaRESUMEN
Adenosine A2A receptor (A2AR) antagonists are the leading nondopaminergic therapy to manage Parkinson's disease (PD) since they afford both motor benefits and neuroprotection. PD begins with a synaptic dysfunction and damage in the striatum evolving to an overt neuronal damage of dopaminergic neurons in the substantia nigra. We tested if A2AR antagonists are equally effective in controlling these two degenerative processes. We used a slow intracerebroventricular infusion of the toxin MPP+ in male rats for 15 days, which caused an initial loss of synaptic markers in the striatum within 10 days, followed by a neuronal loss in the substantia nigra within 30 days. Interestingly, the initial loss of striatal nerve terminals involved a loss of both dopaminergic and glutamatergic synaptic markers, while GABAergic markers were preserved. The daily administration of the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) in the first 10 days after MPP+ infusion markedly attenuated both the initial loss of striatal synaptic markers and the subsequent loss of nigra dopaminergic neurons. Strikingly, the administration of SCH58261 (0.1 mg/kg, i.p. for 10 days) starting 20 days after MPP+ infusion was less efficacious to attenuate the loss of nigra dopaminergic neurons. This prominent A2AR-mediated control of synaptotoxicity was directly confirmed by showing that the MPTP-induced dysfunction (MTT assay) and damage (lactate dehydrogenase release assay) of striatal synaptosomes were prevented by 50 nM SCH58261. This suggests that A2AR antagonists may be more effective to counteract the onset rather than the evolution of PD pathology.
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Antagonistas del Receptor de Adenosina A2 , Cuerpo Estriado , Enfermedad de Parkinson , Receptor de Adenosina A2A , Animales , Ratas , Antagonistas del Receptor de Adenosina A2/farmacología , Antagonistas del Receptor de Adenosina A2/uso terapéutico , Cuerpo Estriado/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Ratas Sprague-Dawley , Receptor de Adenosina A2A/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Sustancia Negra/patología , Triazoles/farmacologíaRESUMEN
INTRODUCTION: Loss of dorsolateral nigral hyperintensity (DNH) on iron-sensitive brain MRI is useful for Parkinson's disease detection. DNH loss could also be of diagnostic value in dementia with Lewy bodies (DLB), an a-synuclein-related pathology. We aim to quantitatively synthesize evidence, investigating the role of MRI, a first-line imaging modality, in early DLB detection and differentiation from other dementias. METHODS: Our study was conducted according to the PRISMA statement. MEDLINE, Scopus, Web of Science, and Cochrane Library were searched using the terms like "dementia with Lewy bodies", "dorsolateral nigral hyperintensity", and "MRI". Only English-written peer-reviewed diagnostic accuracy studies were included. We used QUADAS-2 for quality assessment. RESULTS: Our search yielded 363 search results. Three studies were eligible, all with satisfying, high quality. The total population of 227 patients included 63 with DLB and 164 with other diseases (Alzheimer disease, frontotemporal dementia, mild cognitive impairment). Using a univariate random-effects logistic regression model, our meta-analysis resulted in pooled sensitivity, specificity and DOR of 0.82 [0.62; 0.92], 0.79 [0.70; 0.86] and 16.26 ([3.3276; 79.4702], p = 0.0006), respectively, for scans with mixed field strength (1.5 and 3 T). Subgroup analysis of 3 T scans showed pooled sensitivity, specificity and DOR of 0.82 [0.61; 0.93], 0.82 [0.72; 0.89] and 18.36 ([4.24; 79.46], p < 0.0001), respectively. DISCUSSION: DNH loss on iron-sensitive MRI might comprise a supportive biomarker for DLB detection, that could augment the value of the DLB diagnostic criteria. Further evaluation using standardized protocols is needed, as well as direct comparison to other supportive and indicative biomarkers.
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Enfermedad por Cuerpos de Lewy , Imagen por Resonancia Magnética , Humanos , Enfermedad por Cuerpos de Lewy/diagnóstico por imagen , Enfermedad por Cuerpos de Lewy/diagnóstico , Imagen por Resonancia Magnética/normas , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/patologíaRESUMEN
Recent evidence has supported a pathogenic role for neuroinflammation in Parkinson's disease (PD). Inflammatory response has been associated with symptoms and subtypes of PD. However, it is unclear whether immune changes are involved in the initial pathogenesis of PD, leading to the non-motor symptoms (NMS) observed in its prodromal stage. The current study aimed to characterize the behavioral and cognitive changes in a toxin-induced model of prodromal PD-like syndrome. We also sought to investigate the role of neuroinflammation in prodromal PD-related NMS. Male mice were subjected to bilateral intranasal infusion with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or saline (control group), followed by comprehensive behavioral, pathological and neurochemical analysis. Intranasal MPTP infusion was able to cause the loss of dopaminergic neurons in the substantia nigra (SN). In parallel, it induced impairment in olfactory discrimination and social memory consolidation, compulsive and anxiety-like behaviors, but did not influence motor performance. Iba-1 and GFAP expressions were increased in the SN, suggesting an activated state of microglia and astrocytes. Consistent with this, MPTP mice had increased levels of IL-10 and IL-17A, and decreased levels of BDNF and TrkA mRNA in the SN. The striatum showed increased IL-17A, BDNF, and NFG levels compared to control mice. In conclusion, neuroinflammation may play an important role in the early stage of experimental PD-like syndrome, leading to cognitive and behavioral changes. Our results also indicate that intranasal administration of MPTP may represent a valuable mouse model for prodromal PD.
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Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Síntomas Prodrómicos , Sustancia Negra , Animales , Masculino , Sustancia Negra/metabolismo , Sustancia Negra/patología , Sustancia Negra/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Enfermedades Neuroinflamatorias/patología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Ratones , Microglía/metabolismo , Microglía/patología , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Ansiedad/etiología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacologíaRESUMEN
Asymptomatic Leucine-Rich Repeat Kinase 2 Gene (LRRK2) carriers are at risk for developing Parkinson's disease (PD). We studied presymptomatic substantia nigra pars compacta (SNc) regional neurodegeneration in asymptomatic LRRK2 carriers compared to idiopathic PD patients using neuromelanin-sensitive MRI technique (NM-MRI). Fifteen asymptomatic LRRK2 carriers, 22 idiopathic PD patients, and 30 healthy controls (HCs) were scanned using NM-MRI. We computed volume and contrast-to-noise ratio (CNR) derived from the whole SNc and the sensorimotor, associative, and limbic SNc regions. An analysis of covariance was performed to explore the differences of whole and regional NM-MRI values among the groups while controlling the effect of age and sex. In whole SNc, LRRK2 had significantly lower CNR than HCs but non-significantly higher volume and CNR than PD patients, and PD patients significantly lower volume and CNR compared to HCs. Inside SNc regions, there were significant group effects for CNR in all regions and for volumes in the associative region, with a trend in the sensorimotor region but no significant changes in the limbic region. PD had reduced volume and CNR in all regions compared to HCs. Asymptomatic LRRK2 carriers showed globally decreased SNc volume and CNR suggesting early nigral neurodegeneration in these subjects at risk of developing PD.