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1.
Magnes Res ; 36(4): 69-81, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38953416

RESUMEN

Pathogenic mechanisms implicated in the development of Parkinson disease (PD) are multifaceted and include alpha synuclein aggregation, oxidative stress due to generation of reactive oxygen species (ROS), mitochondrial dysfunction, apoptosis, imbalance of trace elements as well as endoplasmic reticulum stress, and inflammation. Alteration in the homeostasis of bivalent cations, such as iron, magnesium and calcium, has been implicated in the pathogenesis of PD. Low levels of magnesium have been associated with accelerated dopaminergic cell loss in animal PD models, and magnesium has been shown to have a neuroprotective effect in PD models. Evidence of a low magnesium level in the brain of PD individuals, with a low magnesium level in the diet, increasing the risk of PD, further strengthens the role of magnesium deficiency in the pathogenesis of PD. The presence of low-level magnesium in brain tissue and high level in CSF and serum support the possibility of dysfunctional magnesium transporters in PD. Indeed, variants in magnesium transport channels, such as TRPM7 and SLC41A1, have been recently detected in PD individuals. Magnesium, being an NMDA antagonist, could also have a therapeutic role in levodopa-induced dyskinesia. There are no clinical studies indicating a neuroprotective role of magnesium in PD, however, the Mediterranean diet and variants of the diet have been associated with a lower risk of PD, which may be due to the magnesium-rich constituents of the diet. Further clinical trials encompassing therapeutic models to optimize channel function, coupled with a high magnesium diet, may pave the way for promising neuroprotective intervention for PD.


Asunto(s)
Magnesio , Fármacos Neuroprotectores , Enfermedad de Parkinson , Humanos , Magnesio/metabolismo , Magnesio/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Animales
3.
Hum Brain Mapp ; 45(10): e26776, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38958131

RESUMEN

Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine-related changes in large-scale brain network dynamics and its implications in clinical features. We pooled data from two disease-control cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting-state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single-photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age- and sex-matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age- and sex-matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent 18F-DOPA-positron emission tomography (PET) imaging. The striatal synthesis capacity of 18F-DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre-processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k-means clustering were conducted separately for each cohort to derive dFC states (reemerging intra- and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L-dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson's Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large-scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD. PRACTITIONER POINTS: Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD-specific changes in dynamic functional connectivity. Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state. Results only in the PPMI cohort suggest striatal dopamine availability influences large-scale network dynamics that are relevant in motor control.


Asunto(s)
Cuerpo Estriado , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Dopamina , Imagen por Resonancia Magnética , Enfermedad de Parkinson , Tomografía de Emisión de Positrones , Tomografía Computarizada de Emisión de Fotón Único , Humanos , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , Femenino , Masculino , Persona de Mediana Edad , Anciano , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Estudios de Cohortes , Dihidroxifenilalanina/análogos & derivados , Conectoma , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/metabolismo , Red Nerviosa/fisiopatología
4.
Nanotheranostics ; 8(4): 497-505, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38961888

RESUMEN

Goals of the investigation: This work aimed to evaluate the neuroprotective effects of zinc oxide (ZnO) nanoparticles in an experimental mouse model of rotenone-induced PD and investigate the therapeutic effects of ZnO, cobalt ferrite nanoparticles, and their combination. Methods: The levels of dopamine, norepinephrine, epinephrine, and serotonin were assessed using ELISA in the control and experimental model of PD mice. The dopa-decarboxylase expression level was assayed by real-time PCR. The expression level of tyrosine hydroxylase (TH) was assessed by western blot analysis. Results: Our data showed that levels of dopamine decreased in PD mice compared to normal. ZnO NP increased dopamine levels in normal and PD mice (37.5% and 29.5%; respectively, compared to untreated mice). However, ZnO NP did not cause any change in norepinephrine and epinephrine levels either in normal or in PD mice. Levels of serotonin decreased by 64.0%, and 51.1% in PD mice treated with cobalt ferrite and dual ZnO- cobalt ferrite NPs; respectively, when compared to PD untreated mice. The mRNA levels of dopa-decarboxylase increased in both normal and PD mice treated with ZnO NP. Its level decreased when using cobalt ferrite NP and the dual ZnO-cobalt ferrite NP when compared to untreated PD mice. A significant decrease in TH expression by 0.25, 0.68, and 0.62 folds was observed in normal mice treated with ZnO, cobalt ferrite, and the dual ZnO-cobalt ferrite NP as compared to normal untreated mice. In PD mice, ZnO administration caused a non-significant 0.15-fold decrease in TH levels while both cobalt ferrite and the dual ZnO-cobalt ferrite NP administration caused a significant 0.3 and 0.4-fold decrease respectively when compared to untreated PD mice. Principal conclusion: This study reveals that ZnO NPs may be utilized as a potential intervention to elevate dopamine levels to aid in PD treatment.


Asunto(s)
Modelos Animales de Enfermedad , Fármacos Neuroprotectores , Rotenona , Óxido de Zinc , Animales , Óxido de Zinc/farmacología , Óxido de Zinc/química , Ratones , Fármacos Neuroprotectores/farmacología , Masculino , Nanopartículas/química , Compuestos Férricos/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Dopamina/metabolismo , Cobalto/farmacología
5.
Cereb Cortex ; 34(7)2024 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-38967041

RESUMEN

Autonomic symptoms in Parkinson's disease result from variable involvement of the central and peripheral systems, but many aspects remain unclear. The analysis of functional connectivity has shown promising results in assessing the pathophysiology of Parkinson's disease. This study aims to investigate the association between autonomic symptoms and cortical functional connectivity in early Parkinson's disease patients using high-density EEG. 53 early Parkinson's disease patients (F/M 18/35) and 49 controls (F/M 20/29) were included. Autonomic symptoms were evaluated using the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score. Data were recorded with a 64-channel EEG system. We analyzed cortical functional connectivity, based on weighted phase-lag index, in θ-α-ß-low-γ bands. A network-based statistic was used to perform linear regression between Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score and functional connectivity in Parkinson's disease patients. We observed a positive relation between the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score and α-functional connectivity (network τ = 2.8, P = 0.038). Regions with higher degrees were insula and limbic lobe. Moreover, we found positive correlations between the mean connectivity of this network and the gastrointestinal, cardiovascular, and thermoregulatory domains of Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction. Our results revealed abnormal functional connectivity in specific areas in Parkinson's disease patients with greater autonomic symptoms. Insula and limbic areas play a significant role in the regulation of the autonomic system. Increased functional connectivity in these regions might represent the central compensatory mechanism of peripheral autonomic dysfunction in Parkinson's disease.


Asunto(s)
Enfermedades del Sistema Nervioso Autónomo , Electroencefalografía , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/complicaciones , Femenino , Masculino , Persona de Mediana Edad , Anciano , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Enfermedades del Sistema Nervioso Autónomo/etiología , Corteza Insular/diagnóstico por imagen , Corteza Insular/fisiopatología , Sistema Límbico/fisiopatología , Sistema Límbico/diagnóstico por imagen , Vías Nerviosas/fisiopatología , Vías Nerviosas/diagnóstico por imagen
6.
Nat Commun ; 15(1): 5661, 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38969680

RESUMEN

A major challenge in Parkinson's disease is the variability in symptoms and rates of progression, underpinned by heterogeneity of pathological processes. Biomarkers are urgently needed for accurate diagnosis, patient stratification, monitoring disease progression and precise treatment. These were previously lacking, but recently, novel imaging and fluid biomarkers have been developed. Here, we consider new imaging approaches showing sensitivity to brain tissue composition, and examine novel fluid biomarkers showing specificity for pathological processes, including seed amplification assays and extracellular vesicles. We reflect on these biomarkers in the context of new biological staging systems, and on emerging techniques currently in development.


Asunto(s)
Biomarcadores , Encéfalo , Vesículas Extracelulares , Neuroimagen , Enfermedad de Parkinson , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/diagnóstico , Humanos , Biomarcadores/metabolismo , Neuroimagen/métodos , Vesículas Extracelulares/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/patología , Progresión de la Enfermedad
7.
Brain Behav ; 14(7): e3576, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38970157

RESUMEN

PURPOSE: To investigate the potential of magnetic resonance imaging (MRI)-based total and segmental hippocampus volume analysis in the assessment of cognitive status in Parkinson's disease (PD). METHODS: We divided participants into three groups Group A-Parkinson patients (Pp) with normal cognitive status (n = 25), Group B-Pp with dementia (n = 17), and Group C-healthy controls (n = 37). Three-dimensional T1W Fast Spoiled Gradient Recalled Echo images were used for Volbrain hippocampus subfield segmentation. We used the "Winterburn" protocol, which divides the hippocampus into five segments, Cornu Ammonis (CA),CA2/CA3, CA4/dentate gyrus, stratum radiatum, lacunosum, and moleculare, and subiculum. RESULTS: A total of 79 participants were included in the study, consisting of 42 individuals with PD (64.2% male) and 37 healthy controls (54.1% male). The mean age of PD was 60.9 ± 10.7 years and the mean age of control group was 59.27 ± 12.3 years. Significant differences were found in total hippocampal volumes between Group A and B (p = .047. Statistically significant group differences were found in total, right, and left CA1 volumes (analysis of variance [ANOVA]: F(2,76) = 8.098, p = .001; F(2,76) = 7.628, p = .001; F(2,76) = 5.084, p = .008, respectively), as well as in total subiculum volumes (ANOVA: F(2,76) = 4.368, p = .016). Post hoc tests showed that total subiculum volume was significantly lower in individuals with normal cognitive status (0.474 ± 0.116 cm3) compared to healthy controls (0.578 ± 0.151 cm3, p = .013). CONCLUSION: Volumetric hippocampal MRI can be used to assess the cognitive status of Pp. Longitudinal studies that evaluate Pp who progress from normal cognition to dementia are required to establish a causal relationship.


Asunto(s)
Hipocampo , Imagen por Resonancia Magnética , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/diagnóstico por imagen , Masculino , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Imagen por Resonancia Magnética/métodos , Femenino , Persona de Mediana Edad , Anciano , Demencia/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Pruebas Neuropsicológicas , Cognición
8.
Cell Mol Neurobiol ; 44(1): 53, 2024 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-38960968

RESUMEN

Parkinsons disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss and alpha-synuclein aggregation. This comprehensive review examines the intricate role of post-translational modifications (PTMs) in PD pathogenesis, focusing on DNA methylation, histone modifications, phosphorylation, SUMOylation, and ubiquitination. Targeted PTM modulation, particularly in key proteins like Parkin, DJ1, and PINK1, emerges as a promising therapeutic strategy for mitigating dopaminergic degeneration in PD. Dysregulated PTMs significantly contribute to the accumulation of toxic protein aggregates and dopaminergic neuronal dysfunction observed in PD. Targeting PTMs, including epigenetic strategies, addressing aberrant phosphorylation events, and modulating SUMOylation processes, provides potential avenues for intervention. The ubiquitin-proteasome system, governed by enzymes like Parkin and Nedd4, offers potential targets for clearing misfolded proteins and developing disease-modifying interventions. Compounds like ginkgolic acid, SUMO E1 enzyme inhibitors, and natural compounds like Indole-3-carbinol illustrate the feasibility of modulating PTMs for therapeutic purposes in PD. This review underscores the therapeutic potential of PTM-targeted interventions in modulating PD-related pathways, emphasizing the need for further research in this promising area of Parkinsons disease therapeutics.


Asunto(s)
Enfermedad de Parkinson , Procesamiento Proteico-Postraduccional , Humanos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Animales
9.
Sci Rep ; 14(1): 15460, 2024 07 04.
Artículo en Inglés | MEDLINE | ID: mdl-38965287

RESUMEN

The gut microbiota plays a crucial role in neural development and progression of neural disorders like Parkinson's disease (PD). Probiotics have been suggested to impact neurodegenerative diseases via gut-brain axis. This study aims to investigate the therapeutic potential of Lacticaseibacillus rhamnosus E9, a high exopolysaccharide producer, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of PD. C57BL/6 mice subjected to MPTP were fed L. rhamnosus E9 for fifteen days and sacrificed after the last administration. Motor functions were determined by open-field, catalepsy, and wire-hanging tests. The ileum and the brain tissues were collected for ELISA, qPCR, and immunohistochemistry analyses. The cecum content was obtained for microbiota analysis. E9 supplementation alleviated MPTP-induced motor dysfunctions accompanied by decreased levels of striatal TH and dopamine. E9 also reduced the level of ROS in the striatum and decreased the DAT expression while increasing the DR1. Furthermore, E9 improved intestinal integrity by enhancing ZO-1 and Occludin levels and reversed the dysbiosis of the gut microbiota induced by MPTP. In conclusion, E9 supplementation improved the MPTP-induced motor deficits and neural damage as well as intestinal barrier by modulating the gut microbiota in PD mice. These findings suggest that E9 supplementation holds therapeutic potential in managing PD through the gut-brain axis.


Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Lacticaseibacillus rhamnosus , Ratones Endogámicos C57BL , Probióticos , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Lacticaseibacillus rhamnosus/fisiología , Masculino , Probióticos/farmacología , Probióticos/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/microbiología , Cuerpo Estriado/metabolismo , Intoxicación por MPTP/microbiología , Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/tratamiento farmacológico , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/efectos de los fármacos , Dopamina/metabolismo
10.
Exp Dermatol ; 33(7): e15125, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38946225

RESUMEN

The 16th non-collagenous domain (NC16A) of BP180 is the main antigenic target of autoantibodies in bullous pemphigoid (BP) and mucous membrane pemphigoid (MMP). Commercially available assays detect serum autoantibodies against NC16A in the majority of BP (80%-90%) and in approximately 50% of MMP patients. However, a standardized test system for detecting antibodies against other regions of BP180 is still lacking. Moreover, anti-BP180 autoantibodies have been found in neurological conditions such as multiple sclerosis and Parkinson disease. This study aimed at identifying primary epitopes recognized by BP autoantibodies on the BP180 ectodomain. Serum samples of 51 BP and 30 MMP patients both without anti-NC16A reactivity were included along with 44 multiple sclerosis and 75 Parkinson disease sera. Four overlapping His-tagged proteins covering the entire BP180 ectodomain (BP180(ec)1-4) were cloned, expressed, purified and tested for reactivity by immunoblot. IgG antibodies to BP180(ec)3 were detected in 98% of BP, 77% of MMP and 2% of normal human sera. Only weak reactivity was detected for neurological diseases against BP180(ec)1, BP180(ec)2 and BP180(ec)4, in 3%, 11% and 7% of tested multiple sclerosis sera, respectively. 8% of Parkinson disease sera reacted with BP180(ec)2 and 9% with BP180(ec)4. In conclusion, this study successfully identified epitopes recognized by BP autoantibodies outside the NC16A domain in pemphigoid diseases. These findings contribute to a better understanding of the immune response in BP and MMP with potential implications for a future diagnostic assay for NC16A-negative pemphigoid patients.


Asunto(s)
Autoanticuerpos , Autoantígenos , Colágeno Tipo XVII , Esclerosis Múltiple , Colágenos no Fibrilares , Enfermedad de Parkinson , Penfigoide Benigno de la Membrana Mucosa , Penfigoide Ampolloso , Humanos , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/sangre , Colágenos no Fibrilares/inmunología , Penfigoide Ampolloso/inmunología , Penfigoide Ampolloso/sangre , Autoantígenos/inmunología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/sangre , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Penfigoide Benigno de la Membrana Mucosa/inmunología , Penfigoide Benigno de la Membrana Mucosa/sangre , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Epítopos/inmunología , Dominios Proteicos , Femenino , Masculino , Anciano
11.
BMC Neurol ; 24(1): 228, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38951752

RESUMEN

BACKGROUND: Dyspnea is considered a silent threat to people diagnosed with Parkinson's disease and may be a common concern in patients, however, little is known about how it affects quality of life. This study explored the experiences of independently mobile people who are affected by dyspnea in daily life. METHODOLOGY: This was a cross-sectional mixed methods study that included an online questionnaire and semi-structured interviews. The participants were included if they were diagnosed with Parkinson's disease; had a self-reported Hoehn and Yahr Score I, II or III; were mobilizing independently; and were Arabic speakers. Participants were excluded if they had any other musculoskeletal, cardiac, respiratory, or neurological diseases; or were previous or current smokers; or had been previously hospitalized due to respiratory complications. RESULTS: A total of 117 participants completed the Arabic version of the Dyspnea-12 Questionnaire. Dyspnea was reported in all participants and that it had an adverse effect on their quality of life, especially during activities of daily living. Additionally, participants reported a lack of knowledge about pulmonary rehabilitation and were unaware of the availability and potential benefits of participation in programs. CONCLUSION: Dyspnea was reported in people in the early stages (Hoehn and Yahr Stages I, II, and III) of Parkinson's disease, and may benefit from routine assessment of lung function, dyspnea management and participation in pulmonary rehabilitation.


Asunto(s)
Disnea , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/psicología , Enfermedad de Parkinson/diagnóstico , Disnea/etiología , Disnea/diagnóstico , Masculino , Femenino , Estudios Transversales , Anciano , Persona de Mediana Edad , Calidad de Vida/psicología , Encuestas y Cuestionarios , Actividades Cotidianas , Anciano de 80 o más Años
12.
Georgian Med News ; (349): 6-11, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38963193

RESUMEN

A comparative study of the morphological and functional state of the microvasculature of the substantia nigra pars compacta of the brain (SNc) and bone marrow of rats was carried out using the rotenone model of Parkinson's disease (PD) and with subsequent administration of bacterial melanin (BM). The detection of microvasculature was carried out according to the histoangiological method of Chilingaryan. Animal behavior was studied using a cylinder test. An analysis of morphometric data showed that, in comparison with control animals, experimental animals with rotenone dysfunction showed an increase in capillary diameters and a general reduction in the capillary link in SNc. Behavioral tests have shown that the animals with rotenone intoxication exhibit a form of behavior inherent in PD (freezing, immobility, apathy). Under the influence of BM, the diameter of the capillaries in the SNc approaches the norm, and the capillary link is restored. Due to the protective effect of BM in rats with rotenone intoxication, the trophism of the brain tissue increases as a result of the approach of the lumen of the vessels to the norm and the opening of new branches in the capillary network, an increase in the density of capillaries, which ensures the safety of nerve cells. Animal behavior indicators are close to normal. A comprehensive analysis of cytogenetic data of rat bone marrow was also carried out. In animals with PD, compared to controls, there is a significant increase in the amount of polyploid cells (PC) and a decrease in the level of mitotic index (MI), which usually manifests itself in inflammatory processes and is accompanied by inhibition of bone marrow hematopoiesis. Under the influence of BM, a tendency towards normalization of MI was noted and a significant decrease in the percentage of PC was obtained, which possibly indicates its beneficial effect. The data obtained suggest that BM can be used as a therapeutic agent in the treatment of PD.


Asunto(s)
Conducta Animal , Modelos Animales de Enfermedad , Melaninas , Rotenona , Animales , Melaninas/metabolismo , Ratas , Conducta Animal/efectos de los fármacos , Masculino , Médula Ósea/efectos de los fármacos , Enfermedad de Parkinson/patología , Porción Compacta de la Sustancia Negra/efectos de los fármacos , Porción Compacta de la Sustancia Negra/patología , Porción Compacta de la Sustancia Negra/metabolismo , Ratas Wistar , Capilares/efectos de los fármacos , Capilares/patología
13.
Nat Commun ; 15(1): 5540, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38956042

RESUMEN

Iron plays a fundamental role in multiple brain disorders. However, the genetic underpinnings of brain iron and its implications for these disorders are still lacking. Here, we conduct an exome-wide association analysis of brain iron, measured by quantitative susceptibility mapping technique, across 26 brain regions among 26,789 UK Biobank participants. We find 36 genes linked to brain iron, with 29 not being previously reported, and 16 of them can be replicated in an independent dataset with 3,039 subjects. Many of these genes are involved in iron transport and homeostasis, such as FTH1 and MLX. Several genes, while not previously connected to brain iron, are associated with iron-related brain disorders like Parkinson's (STAB1, KCNA10), Alzheimer's (SHANK1), and depression (GFAP). Mendelian randomization analysis reveals six causal relationships from regional brain iron to brain disorders, such as from the hippocampus to depression and from the substantia nigra to Parkinson's. These insights advance our understanding of the genetic architecture of brain iron and offer potential therapeutic targets for brain disorders.


Asunto(s)
Encéfalo , Secuenciación del Exoma , Hierro , Humanos , Hierro/metabolismo , Encéfalo/metabolismo , Masculino , Femenino , Análisis de la Aleatorización Mendeliana , Estudio de Asociación del Genoma Completo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Persona de Mediana Edad , Predisposición Genética a la Enfermedad/genética , Anciano , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Adulto , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo
14.
Sci Rep ; 14(1): 15107, 2024 07 02.
Artículo en Inglés | MEDLINE | ID: mdl-38956066

RESUMEN

Ferroptosis is an iron-dependent cell death form characterized by reactive oxygen species (ROS) overgeneration and lipid peroxidation. Myricetin, a flavonoid that exists in numerous plants, exhibits potent antioxidant capacity. Given that iron accumulation and ROS-provoked dopaminergic neuron death are the two main pathological hallmarks of Parkinson's disease (PD), we aimed to investigate whether myricetin decreases neuronal death through suppressing ferroptosis. The PD models were established by intraperitoneally injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into rats and by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+), respectively. Ferroptosis was identified by assessing the levels of Fe2+, ROS, malondialdehyde (MDA), and glutathione (GSH). The results demonstrated that myricetin treatment effectively mitigated MPTP-triggered motor impairment, dopamine neuronal death, and α-synuclein (α-Syn) accumulation in PD models. Myricetin also alleviated MPTP-induced ferroptosis, as evidenced by decreased levels of Fe2+, ROS, and MDA and increased levels of GSH in the substantia nigra (SN) and serum in PD models. All these changes were reversed by erastin, a ferroptosis activator. In vitro, myricetin treatment restored SH-SY5Y cell viability and alleviated MPP+-induced SH-SY5Y cell ferroptosis. Mechanistically, myricetin accelerated nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and subsequent glutathione peroxidase 4 (Gpx4) expression in MPP+-treated SH-SY5Y cells, two critical inhibitors of ferroptosis. Collectively, these data demonstrate that myricetin may be a potential agent for decreasing dopaminergic neuron death by inhibiting ferroptosis in PD.


Asunto(s)
Modelos Animales de Enfermedad , Neuronas Dopaminérgicas , Ferroptosis , Flavonoides , Especies Reactivas de Oxígeno , Ferroptosis/efectos de los fármacos , Animales , Flavonoides/farmacología , Ratas , Masculino , Especies Reactivas de Oxígeno/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Humanos , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Línea Celular Tumoral , Hierro/metabolismo , alfa-Sinucleína/metabolismo , Ratas Sprague-Dawley , Glutatión/metabolismo , Peroxidación de Lípido/efectos de los fármacos , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Factor 2 Relacionado con NF-E2/metabolismo
15.
Neurology ; 103(3): e209620, 2024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-38986057

RESUMEN

BACKGROUND AND OBJECTIVES: The role of body mass index (BMI) in Parkinson disease (PD) is unclear. Based on the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used 2-sample Mendelian randomization (MR) to replicate a previously reported inverse association of genetically predicted BMI with PD and investigated whether findings were robust in analyses addressing the potential for survival and incidence-prevalence biases. We also examined whether the BMI-PD relation is bidirectional by performing a reverse MR. METHODS: We used summary statistics from a genome-wide association study (GWAS) to extract the association of 501 single-nucleotide polymorphisms (SNPs) with BMI and from the Courage-PD and international Parkinson Disease Genomics Consortium (iPDGC) to estimate their association with PD. Analyses are based on participants of European ancestry. We used the inverse-weighted method to compute odds ratios (ORIVW per 4.8 kg/m2 [95% CI]) of PD and additional pleiotropy robust methods. We performed analyses stratified by age, disease duration, and sex. For reverse MR, we used SNPs associated with PD from 2 iPDGC GWAS to assess the effect of genetic liability toward PD on BMI. RESULTS: Summary statistics for BMI are based on 806,834 participants (54% women). Summary statistics for PD are based on 8,919 (40% women) cases and 7,600 (55% women) controls from Courage-PD, and 19,438 (38% women) cases and 24,388 (51% women) controls from iPDGC. In Courage-PD, we found an inverse association between genetically predicted BMI and PD (ORIVW 0.82 [0.70-0.97], p = 0.012) without evidence for pleiotropy. This association tended to be stronger in younger participants (≤67 years, ORIVW 0.71 [0.55-0.92]) and cases with shorter disease duration (≤7 years, ORIVW 0.75 [0.62-0.91]). In pooled Courage-PD + iPDGC analyses, the association was stronger in women (ORIVW 0.85 [0.74-0.99], p = 0.032) than men (ORIVW 0.92 [0.80-1.04], p = 0.18), but the interaction was not statistically significant (p-interaction = 0.48). In reverse MR, there was evidence for pleiotropy, but pleiotropy robust methods showed a significant inverse association. DISCUSSION: Using an independent data set (Courage-PD), we replicate an inverse association of genetically predicted BMI with PD, not explained by survival or incidence-prevalence biases. Moreover, reverse MR analyses support an inverse association between genetic liability toward PD and BMI, in favor of a bidirectional relation.


Asunto(s)
Índice de Masa Corporal , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Enfermedad de Parkinson , Polimorfismo de Nucleótido Simple , Humanos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/epidemiología , Polimorfismo de Nucleótido Simple/genética , Femenino , Masculino , Persona de Mediana Edad , Anciano , Factores de Riesgo
16.
Med Sci (Paris) ; 40(6-7): 544-549, 2024.
Artículo en Francés | MEDLINE | ID: mdl-38986099

RESUMEN

The enteric nervous system (ENS), often called the "second brain", plays a crucial role in regulating digestive functions. Dysfunctions of the ENS are associated with several diseases such as Parkinson's disease. Recent studies suggest that early digestive disorders, notably chronic constipation, may be early signs of this neurodegenerative disease. Three-dimensional imaging of the ENS offers new insights into early diagnosis, in particular through the analysis of intestinal biopsies. This new research axis raises questions about the intestinal cause of Parkinson's disease, and opens the door to a better understanding and earlier treatment of this disease.


Title: L'intestin, lanceur d'alerte, dans les prémices de la maladie de Parkinson. Abstract: Le système nerveux entérique (SNE), souvent qualifié de « deuxième cerveau ¼, joue un rôle crucial dans la régulation des fonctions digestives. Des dysfonctionnements du SNE sont associés à diverses maladies telles que la maladie de Parkinson. Des études récentes suggèrent que les troubles digestifs précoces, notamment la constipation chronique, pourraient être des signes avant-coureurs de cette maladie neurodégénérative. L'imagerie tridimensionnelle du SNE offre de nouvelles perspectives pour un diagnostic précoce via notamment l'analyse de biopsies intestinales. Ce nouvel axe de recherche soulève des questions sur l'origine intestinale de la maladie de Parkinson et ouvre la porte à une meilleure compréhension et une prise en charge anticipée de cette maladie.


Asunto(s)
Sistema Nervioso Entérico , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/diagnóstico , Sistema Nervioso Entérico/patología , Sistema Nervioso Entérico/fisiopatología , Sistema Nervioso Entérico/fisiología , Diagnóstico Precoz , Tracto Gastrointestinal/patología , Tracto Gastrointestinal/fisiopatología , Tracto Gastrointestinal/fisiología , Animales , Intestinos/patología , Intestinos/fisiología
18.
Int J Biol Sci ; 20(9): 3302-3316, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38993558

RESUMEN

Background: Parkinson's disease (PD) is marked by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor and cognitive dysfunctions. The molecular mechanisms underlying synaptic alterations in PD remain elusive, with a focus on the role of Itga5 in synaptic integrity and motor coordination and TAT-Itga5 was designed to suppress PTEN activity in this investigation. Methods: This study utilized MPTP-induced PD animal models to investigate the expression and role of Itga5 in the striatum. Techniques included quantitative PCR, Western blotting, immunostaining, CRISPR-CasRx-mediated knockdown, electrophysiological assays, behavioral tests, and mass spectrometry. Results: Itga5 expression was significantly reduced in MPTP-induced PD models. In these models, a marked decrease in dendritic spine density and a shift towards thinner spines in striatal GABA neurons were observed, suggesting impaired synaptic integration. Knockdown of Itga5 resulted in reduced dendritic branching, decreased mushroom spines, and increased thin spines, altering synaptic architecture. Electrophysiological analyses revealed changes in action potential and spontaneous excitatory postsynaptic currents, indicating altered synaptic transmission. Motor behavior assessments showed that Itga5 deficiency led to impairments in fine motor control and coordination. Furthermore, Itga5 was found to interact with PTEN, affecting AKT signaling crucial for synaptic development and motor coordination. Conclusion: The study demonstrates that Itga5 plays a critical role in maintaining synaptic integrity and motor coordination in PD. The Itga5-PTEN-AKT pathway represents a potential therapeutic target for addressing synaptic and motor dysfunctions in PD.


Asunto(s)
Fosfohidrolasa PTEN , Enfermedad de Parkinson , Transducción de Señal , Animales , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/genética , Masculino , Ratones , Cuerpo Estriado/metabolismo , Ratones Endogámicos C57BL , Integrina alfa5/metabolismo , Integrina alfa5/genética , Sinapsis/metabolismo , Modelos Animales de Enfermedad
19.
Nat Commun ; 15(1): 5703, 2024 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-38977662

RESUMEN

Explaining predictions for drug repositioning with biological knowledge graphs is a challenging problem. Graph completion methods using symbolic reasoning predict drug treatments and associated rules to generate evidence representing the therapeutic basis of the drug. Yet the vast amounts of generated paths that are biologically irrelevant or not mechanistically meaningful within the context of disease biology can limit utility. We use a reinforcement learning based knowledge graph completion model combined with an automatic filtering approach that produces the most relevant rules and biological paths explaining the predicted drug's therapeutic connection to the disease. In this work we validate the approach against preclinical experimental data for Fragile X syndrome demonstrating strong correlation between automatically extracted paths and experimentally derived transcriptional changes of selected genes and pathways of drug predictions Sulindac and Ibudilast. Additionally, we show it reduces the number of generated paths in two case studies, 85% for Cystic fibrosis and 95% for Parkinson's disease.


Asunto(s)
Descubrimiento de Drogas , Reposicionamiento de Medicamentos , Enfermedad de Parkinson , Humanos , Descubrimiento de Drogas/métodos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Reposicionamiento de Medicamentos/métodos , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Sulindac/farmacología , Sulindac/uso terapéutico , Animales , Algoritmos
20.
BMC Neurosci ; 25(1): 33, 2024 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-38977971

RESUMEN

BACKGROUND: Parkinson's disease (PD), while often associated with its distinctive motor symptoms, can also exert a notable impact on the cardiovascular system due to the development of severe autonomic dysfunction. One of the initial indicators of PD is the appearance of cardiovascular dysautonomia. As such, it is vital to monitor and manage cardiovascular health of individuals with PD, as it may have clinical implications in the development of commonly recognized motor and non-motor aspects of the disease. To study the association of history of cardiovascular disease (CVD) with occurrence and severity of PD, here, we lend data on the association of CVD history with the frequency and the occurrence of idiopathic PD (iPD) using data from the Luxembourg Parkinson's study (iPD n = 676 patients and non-PD n = 874 controls). RESULTS: We report that patients with a history of CVD are at high risk of developing iPD (odds ratio; OR = 1.56, 95% confidence interval; CI 1.09-2.08). This risk is stronger in males and remains significant after adjustment with confounders (OR 1.55, 95% CI 1.05-2.30). This increased susceptibility to iPD is linked to the severity of iPD symptoms mainly the non-motor symptoms of daily living (MDS-UPDRS I) and motor complications (MDS-UPDRS IV) in the affected individuals. CONCLUSION: Individuals with history of CVD have a high risk of developing severe forms of iPD. This observation suggests that careful monitoring and management of patients with a history of cardiac problems may reduce the burden of iPD.


Asunto(s)
Enfermedades Cardiovasculares , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/complicaciones , Masculino , Femenino , Estudios Transversales , Anciano , Persona de Mediana Edad , Enfermedades Cardiovasculares/epidemiología , Factores de Riesgo , Luxemburgo/epidemiología
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