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Central nervous system (CNS)-resident cells such as microglia, oligodendrocytes and astrocytes are gaining increasing attention in respect to their contribution to CNS pathologies including multiple sclerosis (MS). Several studies have demonstrated the involvement of pro-inflammatory glial subsets in the pathogenesis and propagation of inflammatory events in MS and its animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes and microglia can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. Failure of these tissue-protective mechanisms may potentiate disease and increase the risk of conversion to progressive stages of MS, for which currently available therapies are limited. Using proteomic analyses of cerebrospinal fluid specimens from patients with MS in combination with experimental studies, we here identify Heparin-binding EGF-like growth factor (HB-EGF) as a central mediator of tissue-protective and anti-inflammatory effects important for the recovery from acute inflammatory lesions in CNS autoimmunity. Hypoxic conditions drive the rapid upregulation of HB-EGF by astrocytes during early CNS inflammation, while pro-inflammatory conditions suppress trophic HB-EGF signaling through epigenetic modifications. Finally, we demonstrate both anti-inflammatory and tissue-protective effects of HB-EGF in a broad variety of cell types in vitro and use intranasal administration of HB-EGF in acute and post-acute stages of autoimmune neuroinflammation to attenuate disease in a preclinical mouse model of MS. Altogether, we identify astrocyte-derived HB-EGF and its epigenetic regulation as a modulator of autoimmune CNS inflammation and potential therapeutic target in MS.
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Astrócitos , Esclerose Múltipla , Animais , Humanos , Camundongos , Anti-Inflamatórios , Modelos Animais de Doenças , Epigênese Genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Inflamação , ProteômicaRESUMO
The plant homeodomain finger protein Phf8 is a histone demethylase implicated by mutation in mice and humans in neural crest defects and neurodevelopmental disturbances. Considering its widespread expression in cell types of the central nervous system, we set out to determine the role of Phf8 in oligodendroglial cells to clarify whether oligodendroglial defects are a possible contributing factor to Phf8-dependent neurodevelopmental disorders. Using loss- and gain-of-function approaches in oligodendroglial cell lines and primary cell cultures, we show that Phf8 promotes the proliferation of rodent oligodendrocyte progenitor cells and impairs their differentiation to oligodendrocytes. Intriguingly, Phf8 has a strong positive impact on Olig2 expression by acting on several regulatory regions of the gene and changing their histone modification profile. Taking the influence of Olig2 levels on oligodendroglial proliferation and differentiation into account, Olig2 likely acts as an important downstream effector of Phf8 in these cells. In line with such an effector function, ectopic Olig2 expression in Phf8-deficient cells rescues the proliferation defect. Additionally, generation of human oligodendrocytes from induced pluripotent stem cells did not require PHF8 in a system that relies on forced expression of Olig2 during oligodendroglial induction. We conclude that Phf8 may impact nervous system development at least in part through its action in oligodendroglial cells.
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Proliferação de Células , Fator de Transcrição 2 de Oligodendrócitos , Oligodendroglia , Fatores de Transcrição , Oligodendroglia/metabolismo , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Animais , Humanos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Camundongos , Proliferação de Células/fisiologia , Diferenciação Celular/fisiologia , Células Cultivadas , Histona Desmetilases/metabolismo , Histona Desmetilases/genética , Ratos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Células-Tronco Pluripotentes Induzidas/metabolismoRESUMO
Point mutations in the α-synuclein coding gene may lead to the development of Parkinson's disease (PD). PD is often accompanied by other psychiatric conditions, such as anxiety, depression, and drug use disorders, which typically emerge in adulthood. Some of these point mutations, such as SNCA and A30T, have been linked to behavioral effects that are not commonly associated with PD, especially regarding alcohol consumption patterns. In this study, we investigated whether the familial PD point mutation A53T is associated with changes in alcohol consumption behavior and emotional states at ages not yet characterized by α-synuclein accumulation. The affective and alcohol-drinking phenotypes remained unaltered in female PDGF-hA53T-synuclein-transgenic (A53T) mice during both early and late adulthood. Brain region-specific activation of ceramide-producing enzymes, acid sphingomyelinase (ASM), and neutral sphingomyelinase (NSM), known for their neuroprotective properties, was observed during early adulthood but not in late adulthood. In males, the A53T mutation was linked to a reduction in alcohol consumption in both early and late adulthood. However, male A53T mice displayed increased anxiety- and depression-like behaviors during both early and late adulthood. Enhanced ASM activity in the dorsal mesencephalon and ventral hippocampus may potentially contribute to these adverse behavioral effects of the mutation in males during late adulthood. In summary, the A53T gene mutation was associated with diverse changes in emotional states and alcohol consumption behavior long before the onset of PD, and these effects varied by sex. These alterations in behavior may be linked to changes in brain ceramide metabolism.
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Doença de Parkinson , alfa-Sinucleína , Humanos , Camundongos , Masculino , Feminino , Animais , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Camundongos Transgênicos , Esfingomielina Fosfodiesterase , Doença de Parkinson/genética , Mutação , Consumo de Bebidas Alcoólicas/genética , CeramidasRESUMO
Multiple system atrophy (MSA) is a rare and rapidly progressive atypical parkinsonian disorder characterized by oligodendroglial cytoplasmic inclusions containing α-synuclein (α-syn), demyelination, inflammation and neuronal loss. To date, no disease-modifying therapy is available. Targeting α-syn-driven oligodendroglial dysfunction and demyelination presents a potential therapeutic approach for restricting axonal dysfunction, neuronal loss and disease progression. The present study investigated the promyelinogenic potential of sobetirome, a blood-brain barrier permeable and central nervous system selective thyromimetic in the context of an in vitro MSA model. Oligodendrocyte precursor cells (OPCs) were obtained from transgenic mice overexpressing human α-syn specifically in oligodendrocytes (MBP29 mouse line), a well-described MSA model, and non-transgenic littermates. mRNA and protein expression analyses revealed a substantial rescue effect of sobetirome on myelin-specific proteins in control and α-syn overexpressing oligodendrocytes. Furthermore, myelination analysis using nanofibres confirmed that sobetirome increases both the length and number of myelinated segments per oligodendrocyte in primary murine α-syn overexpressing oligodendrocytes and their respective control. These results suggest that sobetirome may be a promising thyromimetic compound targeting an important neuropathological hallmark of MSA.
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Doenças Desmielinizantes , Atrofia de Múltiplos Sistemas , Fenóis , Camundongos , Humanos , Animais , Atrofia de Múltiplos Sistemas/tratamento farmacológico , Atrofia de Múltiplos Sistemas/genética , Atrofia de Múltiplos Sistemas/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Acetatos/metabolismo , Camundongos Transgênicos , Oligodendroglia/metabolismo , Doenças Desmielinizantes/metabolismo , Modelos Animais de DoençasRESUMO
Biallelic loss of SPG11 function constitutes the most frequent cause of complicated autosomal recessive hereditary spastic paraplegia (HSP) with thin corpus callosum, resulting in progressive multisystem neurodegeneration. While the impact of neuroinflammation is an emerging and potentially treatable aspect in neurodegenerative diseases and leukodystrophies, the role of immune cells in SPG11-HSP patients is unknown. Here, we performed a comprehensive immunological characterization of SPG11-HSP, including examination of three human postmortem brain donations, immunophenotyping of patients' peripheral blood cells and patient-specific induced pluripotent stem cell-derived microglia-like cells (iMGL). We delineate a previously unknown role of innate immunity in SPG11-HSP. Neuropathological analysis of SPG11-HSP patient brain tissue revealed profound microgliosis in areas of neurodegeneration, downregulation of homeostatic microglial markers and cell-intrinsic accumulation of lipids and lipofuscin in IBA1+ cells. In a larger cohort of SPG11-HSP patients, the ratio of peripheral classical and intermediate monocytes was increased, along with increased serum levels of IL-6 that correlated with disease severity. Stimulation of patient-specific iMGLs with IFNγ led to increased phagocytic activity compared to control iMGL as well as increased upregulation and release of proinflammatory cytokines and chemokines, such as CXCL10. On a molecular basis, we identified increased STAT1 phosphorylation as mechanism connecting IFNγ-mediated immune hyperactivation and SPG11 loss of function. STAT1 expression was increased both in human postmortem brain tissue and in an Spg11-/- mouse model. Application of an STAT1 inhibitor decreased CXCL10 production in SPG11 iMGL and rescued their toxic effect on SPG11 neurons. Our data establish neuroinflammation as a novel disease mechanism in SPG11-HSP patients and constitute the first description of myeloid cell/ microglia activation in human SPG11-HSP. IFNγ/ STAT1-mediated neurotoxic effects of hyperreactive microglia upon SPG11 loss of function indicate that immunomodulation strategies may slow down disease progression.
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Paraplegia Espástica Hereditária , Animais , Camundongos , Humanos , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/patologia , Doenças Neuroinflamatórias , Proteínas/genética , Neurônios/patologia , MutaçãoRESUMO
OBJECTIVE: The Progressive Supranuclear Palsy quality of life scale (PSP-QoL) has been shown to be a useful tool for capturing health-related quality of life of patients in "everyday life" and in progressive supranuclear palsy (PSP) research. However, at 45 items in length, the questionnaire can take a long time, exhausting PSP patients, in particular if cognitive impaired, which can have a negative impact on the assessment. The aim of this study was to establish a condensed version of the PSP-QoL for research and routine clinical care. METHODS: In this retrospective study, data originating from a German cohort of PSP patients was analyzed. Data from 245 PSP patients were included in this study. The short PSP-QoL questionnaire was created using a two-factor solution and item-total and inter-item correlations for mental and physical aspects of daily living of the PSP-QoL followed by confirmatory factor analysis. RESULTS: The final scale included 12 items representing mental (five items) and physical symptoms (seven items). The specified two-factor model displayed an excellent fit in the confirmatory factor analysis. The short Progressive Supranuclear Palsy Quality of Life scale (PSP-ShoQoL) correlated moderately with the PSP Rating Scale (r [243] = 0.514, P < 0.001) and Geriatric depression scale (r [231] = 0.548, P < 0.001). Sensitivity to change confirmed a significant decrease in QoL after 12 months. DISCUSSION: In this study, we created a 12-item PSP-ShoQoL designed to "facilitate" daily clinical work that correlated strongly with the PSP-QoL and was sensitive to change. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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BACKGROUND AND PURPOSE: Hereditary spastic paraplegias (HSPs) comprise a group of inherited neurodegenerative disorders characterized by progressive spasticity and weakness. Botulinum toxin has been approved for lower limb spasticity following stroke and cerebral palsy, but its effects in HSPs remain underexplored. We aimed to characterize the effects of botulinum toxin on clinical, gait, and patient-reported outcomes in HSP patients and explore the potential of mobile digital gait analysis to monitor treatment effects and predict treatment response. METHODS: We conducted a prospective, observational, multicenter study involving ambulatory HSP patients treated with botulinum toxin tailored to individual goals. Comparing data at baseline, after 1 month, and after 3 months, treatment response was assessed using clinical parameters, goal attainment scaling, and mobile digital gait analysis. Machine learning algorithms were used for predicting individual goal attainment based on baseline parameters. RESULTS: A total of 56 patients were enrolled. Despite the heterogeneity of treatment goals and targeted muscles, botulinum toxin led to a significant improvement in specific clinical parameters and an improvement in specific gait characteristics, peaking at the 1-month and declining by the 3-month follow-up. Significant correlations were identified between gait parameters and clinical scores. With a mean balanced accuracy of 66%, machine learning algorithms identified important denominators to predict treatment response. CONCLUSIONS: Our study provides evidence supporting the beneficial effects of botulinum toxin in HSP when applied according to individual treatment goals. The use of mobile digital gait analysis and machine learning represents a novel approach for monitoring treatment effects and predicting treatment response.
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Análise da Marcha , Paraplegia Espástica Hereditária , Humanos , Masculino , Feminino , Paraplegia Espástica Hereditária/tratamento farmacológico , Adulto , Pessoa de Meia-Idade , Análise da Marcha/métodos , Estudos Prospectivos , Fármacos Neuromusculares/farmacologia , Fármacos Neuromusculares/administração & dosagem , Fármacos Neuromusculares/uso terapêutico , Resultado do Tratamento , Toxinas Botulínicas Tipo A/uso terapêutico , Toxinas Botulínicas Tipo A/farmacologia , Adulto Jovem , Idoso , Toxinas Botulínicas/uso terapêuticoRESUMO
As the CNS-resident macrophages and member of the myeloid lineage, microglia fulfill manifold functions important for brain development and homeostasis. In the context of neurodegenerative diseases, they have been implicated in degenerative and regenerative processes. The discovery of distinct activation patterns, including increased phagocytosis, indicated a damaging role of myeloid cells in multiple system atrophy (MSA), a devastating, rapidly progressing atypical parkinsonian disorder. Here, we analyzed the gene expression profile of microglia in a mouse model of MSA (MBP29-hα-syn) and identified a disease-associated expression profile and upregulation of the colony-stimulating factor 1 (Csf1). Thus, we hypothesized that CSF1 receptor-mediated depletion of myeloid cells using PLX5622 modifies the disease progression and neuropathological phenotype in this mouse model. Intriguingly, sex-balanced analysis of myeloid cell depletion in MBP29-hα-syn mice revealed a two-faced outcome comprising an improved survival rate accompanied by a delayed onset of neurological symptoms in contrast to severely impaired motor functions. Furthermore, PLX5622 reversed gene expression profiles related to myeloid cell activation but reduced gene expression associated with transsynaptic signaling and signal release. While transcriptional changes were accompanied by a reduction of dopaminergic neurons in the SNpc, striatal neuritic density was increased upon myeloid cell depletion in MBP29-hα-syn mice. Together, our findings provide insight into the complex, two-faced role of myeloid cells in the context of MSA emphasizing the importance to carefully balance the beneficial and adverse effects of CSF1R inhibition in different models of neurodegenerative disorders before its clinical translation.SIGNIFICANCE STATEMENT Myeloid cells have been implicated as detrimental in the disease pathogenesis of multiple system atrophy. However, long-term CSF1R-dependent depletion of these cells in a mouse model of multiple system atrophy demonstrates a two-faced effect involving an improved survival associated with a delayed onset of disease and reduced inflammation which was contrasted by severely impaired motor functions, synaptic signaling, and neuronal circuitries. Thus, this study unraveled a complex role of myeloid cells in multiple system atrophy, which indicates important functions beyond the previously described disease-associated, destructive phenotype and emphasized the need of further investigation to carefully and individually fine-tune immunologic processes in different neurodegenerative diseases.
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Atrofia de Múltiplos Sistemas , Animais , Camundongos , Atrofia de Múltiplos Sistemas/genética , Longevidade , Compostos Orgânicos/farmacologia , Microglia/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Modelos Animais de Doenças , Células Mieloides/metabolismo , Receptores de Fator Estimulador de ColôniasRESUMO
The objective of the current study was to optimize the postprocessing pipeline of 7 T chemical exchange saturation transfer (CEST) imaging for reproducibility and to prove this optimization for the detection of age differences and differences between patients with Parkinson's disease versus normal subjects. The following 7 T CEST MRI experiments were analyzed: repeated measurements of a healthy subject, subjects of two age cohorts (14 older, seven younger subjects), and measurements of 12 patients with Parkinson's disease. A slab-selective, B 1 + -homogeneous parallel transmit protocol was used. The postprocessing, consisting of motion correction, smoothing, B 0 -correction, normalization, denoising, B 1 + -correction and Lorentzian fitting, was optimized regarding the intrasubject and intersubject coefficient of variation (CoV) of the amplitudes of the amide pool and the aliphatic relayed nuclear Overhauser effect (rNOE) pool within the brain. Seven "tricks" for postprocessing accomplished an improvement of the mean voxel CoV of the amide pool and the aliphatic rNOE pool amplitudes of less than 5% and 3%, respectively. These postprocessing steps are: motion correction with interpolation of the motion of low-signal offsets (1) using the amide pool frequency offset image as reference (2), normalization of the Z-spectrum using the outermost saturated measurements (3), B 0 correction of the Z-spectrum with moderate spline smoothing (4), denoising using principal component analysis preserving the 11 highest intensity components (5), B 1 + correction using a linear fit (6) and Lorentzian fitting using the five-pool fit model (7). With the optimized postprocessing pipeline, a significant age effect in the amide pool can be detected. Additionally, for the first time, an aliphatic rNOE contrast between subjects with Parkinson's disease and age-matched healthy controls in the substantia nigra is detected. We propose an optimized postprocessing pipeline for CEST multipool evaluation. It is shown that by the use of these seven "tricks", the reproducibility and, thus, the statistical power of a CEST measurement, can be greatly improved and subtle changes can be detected.
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Doença de Parkinson , Humanos , Reprodutibilidade dos Testes , Doença de Parkinson/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Encéfalo , AmidasRESUMO
Pathogenic variants in SPAST, the gene coding for spastin, are the single most common cause of hereditary spastic paraplegia, a progressive motor neuron disease. Spastin regulates key cellular functions, including microtubule-severing and endoplasmic reticulum-morphogenesis. However, it remains unclear how alterations in these cellular functions due to SPAST pathogenic variants result in motor neuron dysfunction. Since spastin influences both microtubule network and endoplasmic reticulum structure, we hypothesized that spastin is necessary for the regulation of Ca2+ homeostasis via store-operated calcium entry. Here, we show that the lack of spastin enlarges the endoplasmic reticulum and reduces store-operated calcium entry. In addition, elevated levels of different spastin variants induced clustering of STIM1 within the endoplasmic reticulum, altered the transport of STIM1 to the plasma membrane and reduced store-operated calcium entry, which could be rescued by exogenous expression of STIM1. Importantly, store-operated calcium entry was strongly reduced in induced pluripotent stem cell-derived neurons from hereditary spastic paraplegia patients with pathogenic variants in SPAST resulting in spastin haploinsufficiency. These neurons developed axonal swellings in response to lack of spastin. We were able to rescue both store-operated calcium entry and axonal swellings in SPAST patient neurons by restoring spastin levels, using CRISPR/Cas9 to correct the pathogenic variants in SPAST. These findings demonstrate that proper amounts of spastin are a key regulatory component for store-operated calcium entry mediated Ca2+ homeostasis and suggest store-operated calcium entry as a disease relevant mechanism of spastin-linked motor neuron disease.
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Paraplegia Espástica Hereditária , Cálcio/metabolismo , Humanos , Microtúbulos , Neurônios Motores/metabolismo , Espastina/genéticaRESUMO
Understanding of the human body's internal processes to maintain balance is fundamental to simulate postural control behaviour. The body uses multiple sensory systems' information to obtain a reliable estimate about the current body state. This information is used to control the reactive behaviour to maintain balance. To predict a certain motion behaviour with knowledge of the muscle forces, forward dynamic simulations of biomechanical human models can be utilized. We aim to use predictive postural control simulations to give therapy recommendations to patients suffering from postural disorders in the future. It is important to know which types of modelling approaches already exist to apply such predictive forward dynamic simulations. Current literature provides different models that aim to simulate human postural control. We conducted a systematic literature research to identify the different approaches of postural control models. The different approaches are discussed regarding their applied biomechanical models, sensory representation, sensory integration, and control methods in standing and gait simulations. We searched on Scopus, Web of Science and PubMed using a search string, scanned 1253 records, and found 102 studies to be eligible for inclusion. The included studies use different ways for sensory representation and integration, although underlying neural processes still remain unclear. We found that for postural control optimal control methods like linear quadratic regulators and model predictive control methods are used less, when models' level of details is increasing, and nonlinearities become more important. Considering musculoskeletal models, reflex-based and PD controllers are mainly applied and show promising results, as they aim to create human-like motion behaviour considering physiological processes.
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Marcha , Equilíbrio Postural , Humanos , Movimento (Física) , Músculos , ReflexoRESUMO
The alteration and aggregation of alpha-synuclein (α-syn) play a crucial role in neurodegenerative diseases collectively termed as synucleinopathies, including Parkinson's disease (PD). The bidirectional interaction of α-syn with lipids and biomembranes impacts not only α-syn aggregation but also lipid homeostasis. Indeed, lipid composition and metabolism are severely perturbed in PD. One explanation for lipid-associated alterations may involve structural changes in α-syn, caused, for example, by missense mutations in the lipid-binding region of α-syn as well as post-translational modifications such as phosphorylation, acetylation, nitration, ubiquitination, truncation, glycosylation, and glycation. Notably, different strategies targeting the α-syn-lipid interaction have been identified and are able to reduce α-syn pathology. These approaches include the modulation of post-translational modifications aiming to reduce the aggregation of α-syn and modify its binding properties to lipid membranes. Furthermore, targeting enzymes involved in various steps of lipid metabolism and exploring the neuroprotective potential of lipids themselves have emerged as novel therapeutic approaches. Taken together, this review focuses on the bidirectional crosstalk of α-syn and lipids and how alterations of this interaction affect PD and thereby open a window for therapeutic interventions.
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Doença de Parkinson , Sinucleinopatias , alfa-Sinucleína , Humanos , Sistema Nervoso Central , LipídeosRESUMO
Recently, oligodendrocytes (Ol) have been attributed potential immunomodulatory effects. Yet, the exact mode of interaction with pathogenic CNS infiltrating lymphocytes remains unclear. Here, we attempt to dissect mechanisms of Ol modulation during neuroinflammation and characterize the interaction of Ol with pathogenic T cells. RNA expression analysis revealed an upregulation of immune-modulatory genes and adhesion molecules (AMs), ICAM-1 and VCAM-1, in Ol when isolated from mice undergoing experimental autoimmune encephalomyelitis (EAE). To explore whether AMs are involved in the interaction of Ol with infiltrating T cells, we performed co-culture studies on mature Ol and Th1 cells. Live cell imaging analysis showed direct interaction between both cell types. Eighty percentage of Th1 cells created contacts with Ol that lasted longer than 15 min, which may be regarded as physiologically relevant. Exposure of Ol to Th1 cells or their supernatant resulted in a significant extension of Ol processes, and upregulation of AMs as well as other immunomodulatory genes. Our observations indicate that blocking of oligodendroglial ICAM-1 can reduce the number of Th1 cells initially contacting the Ol. These results suggest that AMs may play a role in the interaction between Ol and Th1 cells. We identified Ol interacting with CD4+ cells in vivo in spinal cord tissue of EAE diseased mice indicating that our in vitro findings are of interest to further scientific research in this field. Further characterization and understanding of Ol interaction with infiltrating cells may lead to new therapeutic strategies enhancing Ol protection and remyelination potential. Oligodendrocytes regulate immune modulatory genes and adhesion molecules during autoimmune neuroinflammation Oligodendrocytes interact with Th1 cells in vitro in a physiologically relevant manner Adhesion molecules may be involved in Ol-Th1 cell interaction.
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Encefalomielite Autoimune Experimental , Molécula 1 de Adesão Intercelular/metabolismo , Animais , Encefalomielite Autoimune Experimental/patologia , Molécula 1 de Adesão Intercelular/genética , Camundongos , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias , Oligodendroglia/metabolismoRESUMO
OBJECTIVE: Parkinson disease (PD) has useful symptomatic treatments that do not slow the neurodegenerative process, and no significant disease-modifying treatments are approved. A key therapeutic target in PD is α-synuclein (αS), which is both genetically implicated and accumulates in Lewy bodies rich in vesicles and other lipid membranes. Reestablishing αS homeostasis is a central goal in PD. Based on previous lipidomic analyses, we conducted a mouse trial of a stearoyl-coenzyme A desaturase (SCD) inhibitor ("5b") that prevented αS-positive vesicular inclusions and cytotoxicity in cultured human neurons. METHODS: Oral dosing and brain activity of 5b were established in nontransgenic mice. 5b in drinking water was given to mice expressing wild-type human αS (WT) or an amplified familial PD αS mutation (E35K + E46K + E61K ["3K"]) beginning near the onset of nigral and cortical neurodegeneration and the robust PD-like motor syndrome in 3K. Motor phenotypes, brain cytopathology, and SCD-related lipid changes were quantified in 5b- versus placebo-treated mice. Outcomes were compared to effects of crossing 3K to SCD1-/- mice. RESULTS: 5b treatment reduced αS hyperphosphorylation in E46K-expressing human neurons, in 3K neural cultures, and in both WT and 3K αS mice. 5b prevented subtle gait deficits in WT αS mice and the PD-like resting tremor and progressive motor decline of 3K αS mice. 5b also increased αS tetramers and reduced proteinase K-resistant lipid-rich aggregates. Similar benefits accrued from genetically deleting 1 SCD allele, providing target validation. INTERPRETATION: Prolonged reduction of brain SCD activity prevented PD-like neuropathology in multiple PD models. Thus, an orally available SCD inhibitor potently ameliorates PD phenotypes, positioning this approach to treat human α-synucleinopathies. ANN NEUROL 2021;89:74-90.
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Doença de Parkinson/prevenção & controle , alfa-Sinucleína/genética , Animais , Encéfalo/patologia , Humanos , Corpos de Lewy/patologia , Camundongos Transgênicos , Neurônios/metabolismo , Doença de Parkinson/genética , Fenótipo , alfa-Sinucleína/metabolismoRESUMO
Motor-cognitive dual tasks are used to investigate the interplay between gait and cognition. Dual task walking in patients with Parkinson's disease (PD) results in decreased gait speed and more importantly in an increased fall risk. There is evidence that physical training may improve gait during dual task challenge. Physiotherapy and treadmill walking are known to improve single task gait. The aim of this study was to investigate the impact of individualized physiotherapy or treadmill training on gait during dual task performance. 105 PD patients were randomly assigned to an intervention group (physiotherapy or treadmill). Both groups received 10 individual interventional sessions of 25 min each and additional group therapy sessions for 14 days. Primary outcome measure was the dual task gait speed. Secondary outcomes were additional gait parameters during dual task walking, UPDRS-III, BBS and walking capacity. All gait parameters were recorded using sensor-based gait analysis. Gait speed improved significantly by 4.2% (treadmill) and 8.3% (physiotherapy). Almost all secondary gait parameters, UPDRS-III, BBS, and walking capacity improved significantly and similarly in both groups. However, interaction effects were not observed. Both interventions significantly improved gait in patients with mild to moderate PD. However, treadmill walking did not show significant benefits compared to individualized physiotherapy. Our data suggest that both interventions improve dual task walking and therefore support safe and independent walking. This result may lead to more tailored therapeutic preferences.
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Doença de Parkinson , Teste de Esforço , Terapia por Exercício/métodos , Marcha , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/terapia , Modalidades de Fisioterapia , CaminhadaRESUMO
Developing machine learning algorithms for time-series data often requires manual annotation of the data. To do so, graphical user interfaces (GUIs) are an important component. Existing Python packages for annotation and analysis of time-series data have been developed without addressing adaptability, usability, and user experience. Therefore, we developed a generic open-source Python package focusing on adaptability, usability, and user experience. The developed package, Machine Learning and Data Analytics (MaD) GUI, enables developers to rapidly create a GUI for their specific use case. Furthermore, MaD GUI enables domain experts without programming knowledge to annotate time-series data and apply algorithms to it. We conducted a small-scale study with participants from three international universities to test the adaptability of MaD GUI by developers and to test the user interface by clinicians as representatives of domain experts. MaD GUI saves up to 75% of time in contrast to using a state-of-the-art package. In line with this, subjective ratings regarding usability and user experience show that MaD GUI is preferred over a state-of-the-art package by developers and clinicians. MaD GUI reduces the effort of developers in creating GUIs for time-series analysis and offers similar usability and user experience for clinicians as a state-of-the-art package.
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Software , Interface Usuário-Computador , Algoritmos , Humanos , Aprendizado de MáquinaRESUMO
Inflammatory bowel disease (IBD) comprises Crohn's disease (CD) and ulcerative colitis (UC) and is associated with neuropsychiatric symptoms like anxiety and depression. Both conditions strongly worsen IBD disease burden. In the present review, we summarize the current understanding of the pathogenesis of depression and anxiety in IBD. We present a stepwise cascade along a gut-immune-brain axis initiated by evasion of chronic intestinal inflammation to pass the epithelial and vascular barrier in the gut and cause systemic inflammation. We then summarize different anatomical transmission routes of gut-derived peripheral inflammation into the central nervous system (CNS) and highlight the current knowledge on neuroinflammatory changes in the CNS of preclinical IBD mouse models with a focus on microglia, the brain-resident macrophages. Subsequently, we discuss how neuroinflammation in IBD can alter neuronal circuitry to trigger symptoms like depression and anxiety. Finally, the role of intestinal microbiota in the gut-immune-brain axis in IBD will be reviewed. A more comprehensive understanding of the interaction between the gastrointestinal tract, the immune system and the CNS accounting for the similarities and differences between UC and CD will pave the path for improved prediction and treatment of neuropsychiatric comorbidities in IBD and other inflammatory diseases.
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Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Animais , Encéfalo/patologia , Colite Ulcerativa/patologia , Doença de Crohn/patologia , Inflamação , Doenças Inflamatórias Intestinais/patologia , Camundongos , MorbidadeRESUMO
Parkinson's disease (PD) is neuropathologically characterized by the loss of dopaminergic neurons and the deposition of aggregated alpha synuclein (aSyn). Mounting evidence suggests that neuritic degeneration precedes neuronal loss in PD. A possible underlying mechanism could be the interference of aSyn with microtubule organization in the neuritic development, as implied by several studies using cell-free model systems. In this study, we investigate the impact of aSyn on microtubule organization in aSyn overexpressing H4 neuroglioma cells and midbrain dopaminergic neuronal cells (mDANs) generated from PD patient-derived human induced pluripotent stem cells (hiPSCs) carrying an aSyn gene duplication (SNCADupl). An unbiased mass spectrometric analysis reveals a preferential binding of aggregated aSyn conformers to a number of microtubule elements. We confirm the interaction of aSyn with beta tubulin III in H4 and hiPSC-derived mDAN cell model systems, and demonstrate a remarkable redistribution of tubulin isoforms from the soluble to insoluble fraction, accompanied by a significantly increased insoluble aSyn level. Concordantly, SNCADupl mDANs show impaired neuritic phenotypes characterized by perturbations in neurite initiation and outgrowth. In summary, our findings suggest a mechanistic pathway, through which aSyn aggregation interferes with microtubule organization and induces neurite impairments.
Assuntos
Células-Tronco Pluripotentes Induzidas , Doença de Parkinson , alfa-Sinucleína , Neurônios Dopaminérgicos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Microtúbulos/metabolismo , Neuritos/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMO
Since the seminal works by Brodmann and contemporaries, it is well-known that different brain regions exhibit unique cytoarchitectonic and myeloarchitectonic features. Transferring the approach of classifying brain tissues - and other tissues - based on their intrinsic features to the realm of magnetic resonance (MR) is a longstanding endeavor. In the 1990s, atlas-based segmentation replaced earlier multi-spectral classification approaches because of the large overlap between the class distributions. Here, we explored the feasibility of performing global brain classification based on intrinsic MR features, and used several technological advances: ultra-high field MRI, q-space trajectory diffusion imaging revealing voxel-intrinsic diffusion properties, chemical exchange saturation transfer and semi-solid magnetization transfer imaging as a marker of myelination and neurochemistry, and current neural network architectures to analyze the data. In particular, we used the raw image data as well to increase the number of input features. We found that a global brain classification of roughly 97 brain regions was feasible with gross classification accuracy of 60%; and that mapping from voxel-intrinsic MR data to the brain region to which the data belongs is possible. This indicates the presence of unique MR signals of different brain regions, similar to their cytoarchitectonic and myeloarchitectonic fingerprints.
Assuntos
Mapeamento Encefálico/métodos , Encéfalo/diagnóstico por imagem , Análise de Dados , Aprendizado de Máquina , Imageamento por Ressonância Magnética/métodos , Rede Nervosa/diagnóstico por imagem , Adulto , Idoso , Mapeamento Encefálico/classificação , Feminino , Humanos , Aprendizado de Máquina/classificação , Imageamento por Ressonância Magnética/classificação , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Spastic paraplegia gene 11(SPG11)-linked hereditary spastic paraplegia is a complex monogenic neurodegenerative disease that in addition to spastic paraplegia is characterized by childhood onset cognitive impairment, thin corpus callosum and enlarged ventricles. We have previously shown impaired proliferation of SPG11 neural progenitor cells (NPCs). For the delineation of potential defect in SPG11 brain development we employ 2D culture systems and 3D human brain organoids derived from SPG11 patients' iPSC and controls. We reveal that an increased rate of asymmetric divisions of NPCs leads to proliferation defect, causing premature neurogenesis. Correspondingly, SPG11 organoids appeared smaller than controls and had larger ventricles as well as thinner germinal wall. Premature neurogenesis and organoid size were rescued by GSK3 inhibititors including the Food and Drug Administration-approved tideglusib. These findings shed light on the neurodevelopmental mechanisms underlying disease pathology.