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1.
PLoS One ; 19(3): e0297143, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427645

RESUMO

The sequential pathology of Kyasanur forest disease (KFD) in mouse brain was assessed in this study. Kyasanur forest disease virus (KFDV) strain P9605 used in this study was confirmed by real-time reverse transcriptase-polymerase chain reaction targeting the NS5 gene. Mouse Lethal Dose 50 (MLD50) of the virus was determined by in-vivo mice inoculation test. One MLD50 of the KFDV was inoculated intra-cerebrally into 36 mice aged 2-3 weeks. Another group of 36 age-matched mice that served as control group were inoculated with plain media. Six mice each from infected and control groups were euthanized every 24 hrs intervals for six days. Brain tissues were collected in 10% NBF. The collected brain tissues were processed and subjected to histopathological studies by Hematoxylin and Eosin staining. Grossly, the infected mice showed symptoms of dullness, hunched back appearance, weakness, sluggish movements with indication of hind quarter paralysis on day four post-infection. These symptoms got aggravated with complete paralysis of the hind quarters, inability to move and death on 5th and 6th day post-infection. Microscopically, the brain showed apoptosis of neurons, perivascular cuffing, gliosis, congestion, neuropil vacuolation, meningitis, degeneration, and necrotic neurons. The real-time RT-PCR on hippocampus of the KFDV-infected mouse brain showed three-fold higher expression levels of Caspase 3, a crucial mediator of apoptosis. The cerebral cortex, cerebellum and hippocampus that control the motor neuron activities and muscle tone were primarily affected, possibly correlating with the gross symptoms of hind quarter paralysis, ataxia, and other motor neuron dysfunctions noticed. Taken together, these findings reveal that KFDV induces apoptosis of neurons in the cerebrum and hippocampus of KFDV infected mice. Further studies are needed to confirm if the lesions noticed in mice brain simulate the brain lesions in humans since gross motor-neuron symptoms are similar in mice as well as humans.


Assuntos
Vírus da Encefalite Transmitidos por Carrapatos , Doença da Floresta de Kyasanur , Humanos , Animais , Camundongos , Vírus da Encefalite Transmitidos por Carrapatos/genética , Encéfalo/patologia , Córtex Cerebral/patologia , Hipocampo/patologia , Apoptose , Neurônios Motores/patologia , Paralisia
2.
Cells ; 13(5)2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38474399

RESUMO

Numerous reports have demonstrated the breakdown of the blood-CNS barrier (B-CNS-B) in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. Re-establishing barrier integrity in the CNS is critical to prevent further motor neuron degeneration from harmful components in systemic circulation. Potential therapeutic strategies for repairing the B-CNS-B may be achieved by the replacement of damaged endothelial cells (ECs) via stem cell administration or enhancement of endogenous EC survival through the delivery of bioactive particles secreted by stem cells. These cellular and noncellular approaches are thoroughly discussed in the present review. Specific attention is given to certain stem cell types for EC replacement. Also, various nanoparticles secreted by stem cells as well as other biomolecules are elucidated as promising agents for endogenous EC repair. Although the noted in vitro and in vivo studies show the feasibility of the proposed therapeutic approaches to the repair of the B-CNS-B in ALS, further investigation is needed prior to clinical transition.


Assuntos
Esclerose Amiotrófica Lateral , Doenças Neurodegenerativas , Humanos , Esclerose Amiotrófica Lateral/metabolismo , Células Endoteliais/metabolismo , Doenças Neurodegenerativas/metabolismo , Neurônios Motores/metabolismo , Células-Tronco/metabolismo
3.
Acta Neuropathol ; 147(1): 56, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38478117

RESUMO

The stimulator of interferon genes (STING) pathway has been implicated in neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis (ALS). While prior studies have focused on STING within immune cells, little is known about STING within neurons. Here, we document neuronal activation of the STING pathway in human postmortem cortical and spinal motor neurons from individuals affected by familial or sporadic ALS. This process takes place selectively in the most vulnerable cortical and spinal motor neurons but not in neurons that are less affected by the disease. Concordant STING activation in layer V cortical motor neurons occurs in a mouse model of C9orf72 repeat-associated ALS and frontotemporal dementia (FTD). To establish that STING activation occurs in a neuron-autonomous manner, we demonstrate the integrity of the STING signaling pathway, including both upstream activators and downstream innate immune response effectors, in dissociated mouse cortical neurons and neurons derived from control human induced pluripotent stem cells (iPSCs). Human iPSC-derived neurons harboring different familial ALS-causing mutations exhibit increased STING signaling with DNA damage as a main driver. The elevated downstream inflammatory markers present in ALS iPSC-derived neurons can be suppressed with a STING inhibitor. Our results reveal an immunophenotype that consists of innate immune signaling driven by the STING pathway and occurs specifically within vulnerable neurons in ALS/FTD.


Assuntos
Esclerose Amiotrófica Lateral , Demência Frontotemporal , Células-Tronco Pluripotentes Induzidas , Doença de Pick , Animais , Humanos , Camundongos , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Proteína C9orf72/genética , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios Motores/metabolismo
4.
BMC Neurol ; 24(1): 93, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38468256

RESUMO

BACKGROUND: Spinal muscular atrophy (SMA) is a rare autosomal recessive hereditary neuromuscular disease caused by survival motor neuron 1 (SMN1) gene deletion or mutation. Homozygous deletions of exon 7 in SMN1 result in 95% of SMA cases, while the remaining 5% are caused by other pathogenic variants of SMN1. METHODS: We analyzed two SMA-suspected cases that were collected, with no SMN1 gene deletion and point mutation in whole-exome sequencing. Exon 1 deletion of the SMN gene was detected using Multiplex ligation-dependent probe amplification (MLPA) P021. We used long-range polymerase chain reaction (PCR) to isolate the SMN1 template, optimized-MLPA P021 for copy number variation (CNV) analysis within SMN1 only, and validated the findings via third-generation sequencing. RESULTS: Two unrelated families shared a genotype with one copy of exon 7 and a novel variant, g.70919941_70927324del, in isolated exon 1 of the SMN1 gene. Case F1-II.1 demonstrated no exon 1 but retained other exons, whereas F2-II.1 had an exon 1 deletion in a single SMN1 gene. The read coverage in the third-generation sequencing results of both F1-II.1 and F2-II.1 revealed a deletion of approximately 7.3 kb in the 5' region of SMN1. The first nucleotide in the sequence data aligned to the 7385 bp of NG_008691.1. CONCLUSION: Remarkably, two proband families demonstrated identical SMN1 exon 1 breakpoint sites, hinting at a potential novel mutation hotspot in Chinese SMA, expanding the variation spectrum of the SMN1 gene and corroborating the specificity of isolated exon 1 deletion in SMA pathogenesis. The optimized-MLPA P021 determined a novel variant (g.70919941_70927324del) in isolated exon 1 of the SMN1 gene based on long-range PCR, enabling efficient and affordable detection of SMN gene variations in patients with SMA, providing new insight into SMA diagnosis to SMN1 deficiency and an optimized workflow for single exon CNV testing of the SMN gene.


Assuntos
Reação em Cadeia da Polimerase Multiplex , Atrofia Muscular Espinal , Humanos , Variações do Número de Cópias de DNA/genética , Fluxo de Trabalho , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Neurônios Motores , Éxons/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética
5.
Acta Neuropathol ; 147(1): 53, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38470509

RESUMO

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by recessive pathogenic variants affecting the survival of motor neuron (SMN1) gene (localized on 5q). In consequence, cells lack expression of the corresponding protein. This pathophysiological condition is clinically associated with motor neuron (MN) degeneration leading to severe muscular atrophy. Additionally, vulnerability of other cellular populations and tissues including skeletal muscle has been demonstrated. Although the therapeutic options for SMA have considerably changed, treatment responses may differ thus underlining the persistent need for validated biomarkers. To address this need and to identify novel marker proteins for SMA, we performed unbiased proteomic profiling on cerebrospinal fluid derived (CSF) from genetically proven SMA type 1-3 cases and afterwards performed ELISA studies on CSF and serum samples to validate the potential of a novel biomarker candidates in both body fluids. To further decipher the pathophysiological impact of this biomarker, immunofluorescence studies were carried out on spinal cord and skeletal muscle derived from a 5q-SMA mouse model. Proteomics revealed increase of LARGE1 in CSF derived from adult patients showing a clinical response upon treatment with nusinersen. Moreover, LARGE1 levels were validated in CSF samples of further SMA patients (type 1-3) by ELISA. These studies also unveiled a distinguishment between groups in improvement of motor skills: adult patients do present with lowered level per se at baseline visit while no elevation upon treatment in the pediatric cohort can be observed. ELISA-based studies of serum samples showed no changes in the pediatric cohort but unraveled elevated level in adult patients responding to future intervention with nusinersen, while non-responders did not show a significant increase. Additional immunofluorescence studies of LARGE1 in MN and skeletal muscle of a SMA type 3 mouse model revealed an increase of LARGE1 during disease progression. Our combined data unraveled LARGE1 as a protein dysregulated in serum and CSF of SMA-patients (and in MN and skeletal muscle of SMA mice) holding the potential to serve as a disease marker for SMA and enabling to differentiate between patients responding and non-responding to therapy with nusinersen.


Assuntos
Atrofia Muscular Espinal , Atrofias Musculares Espinais da Infância , Adulto , Humanos , Criança , Camundongos , Animais , Proteômica , Atrofia Muscular Espinal/genética , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Atrofias Musculares Espinais da Infância/patologia , Neurônios Motores/patologia , Biomarcadores/líquido cefalorraquidiano , Modelos Animais de Doenças
6.
Cells ; 13(5)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38474336

RESUMO

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the degeneration of motor neurons. Mutations in the cyclin F (CCNF) and fused in sarcoma (FUS) genes have been associated with ALS pathology. In this study, we aimed to investigate the functional role of CCNF and FUS in ALS by using genome editing techniques to generate zebrafish models with genetic disruptions in these genes. Sequence comparisons showed significant homology between human and zebrafish CCNF and FUS proteins. We used CRISPR/Cas9 and TALEN-mediated genome editing to generate targeted disruptions in the zebrafish ccnf and fus genes. Ccnf-deficient zebrafish exhibited abnormal motor neuron development and axonal outgrowth, whereas Fus-deficient zebrafish did not exhibit developmental abnormalities or axonopathies in primary motor neurons. However, Fus-deficient zebrafish displayed motor impairments in response to oxidative and endoplasmic reticulum stress. The Ccnf-deficient zebrafish were only sensitized to endoplasmic reticulum stress, indicating that ALS genes have overlapping as well as unique cellular functions. These zebrafish models provide valuable platforms for studying the functional consequences of CCNF and FUS mutations in ALS pathogenesis. Furthermore, these zebrafish models expand the drug screening toolkit used to evaluate possible ALS treatments.


Assuntos
Esclerose Amiotrófica Lateral , Ciclinas , Doenças Neurodegenerativas , Proteína FUS de Ligação a RNA , Peixe-Zebra , Animais , Humanos , Esclerose Amiotrófica Lateral/metabolismo , Ciclinas/metabolismo , Neurônios Motores/patologia , Doenças Neurodegenerativas/metabolismo , Proteínas/metabolismo , Proteína FUS de Ligação a RNA/genética , Proteína FUS de Ligação a RNA/metabolismo , Peixe-Zebra/metabolismo
7.
Skelet Muscle ; 14(1): 5, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38454511

RESUMO

BACKGROUND: Neurovascular cells have wide-ranging implications on skeletal muscle biology regulating myogenesis, maturation, and regeneration. Although several in vitro studies have investigated how motor neurons and endothelial cells interact with skeletal myocytes independently, there is limited knowledge about the combined effect of neural and vascular cells on muscle maturation and development. METHODS: Here, we report a triculture system comprising human-induced pluripotent stem cell (iPSC)-derived skeletal myocytes, human iPSC-derived motor neurons, and primary human endothelial cells maintained under controlled media conditions. Briefly, iPSCs were differentiated to generate skeletal muscle progenitor cells (SMPCs). These SMPCs were seeded at a density of 5 × 104 cells/well in 12-well plates and allowed to differentiate for 7 days before adding iPSC-derived motor neurons at a concentration of 0.5 × 104 cells/well. The neuromuscular coculture was maintained for another 7 days in coculture media before addition of primary human umbilical vein endothelial cells (HUVEC) also at 0.5 × 104 cells/well. The triculture was maintained for another 7 days in triculture media comprising equal portions of muscle differentiation media, coculture media, and vascular media. Extensive morphological, genetic, and molecular characterization was performed to understand the combined and individual effects of neural and vascular cells on skeletal muscle maturation. RESULTS: We observed that motor neurons independently promoted myofiber fusion, upregulated neuromuscular junction genes, and maintained a molecular niche supportive of muscle maturation. Endothelial cells independently did not support myofiber fusion and downregulated expression of LRP4 but did promote expression of type II specific myosin isoforms. However, neurovascular cells in combination exhibited additive increases in myofiber fusion and length, enhanced production of Agrin, along with upregulation of several key genes like MUSK, RAPSYN, DOK-7, and SLC2A4. Interestingly, more divergent effects were observed in expression of genes like MYH8, MYH1, MYH2, MYH4, and LRP4 and secretion of key molecular factors like amphiregulin and IGFBP-4. CONCLUSIONS: Neurovascular cells when cultured in combination with skeletal myocytes promoted myocyte fusion with concomitant increase in expression of various neuromuscular genes. This triculture system may be used to gain a deeper understanding of the effects of the neurovascular niche on skeletal muscle biology and pathophysiology.


Assuntos
Células-Tronco Pluripotentes Induzidas , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células Endoteliais , Células Cultivadas , Fibras Musculares Esqueléticas/metabolismo , Neurônios Motores , Diferenciação Celular/fisiologia
8.
J Electromyogr Kinesiol ; 75: 102872, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38458102

RESUMO

The number of motor units included in calculations of mean firing rates varies widely in the literature. It is unknown how the number of decomposed motor units included in the calculation of firing rate per participant compares to the total number of active motor units in the muscle, and if this is different for males and females. Bootstrapped distributions and confidence intervals (CI) of mean motor unit firing rates decomposed from the tibialis anterior were used to represent the total number of active motor units for individual participants in trials from 20 to 100 % of maximal voluntary contraction. Bootstrapped distributions of mean firing rates were constructed using different numbers of motor units, from one to the maximum number for each participant, and compared to the CIs. A probability measure for each number of motor units involved in firing rate was calculated and then averaged across all individuals. Motor unit numbers required for similar levels of probability increased as contraction intensity increased (p < 0.001). Increased levels of probability also required higher numbers of motor units (p < 0.001). There was no effect of sex (p ≥ 0.97) for any comparison. This methodology should be repeated in other muscles, and aged populations.


Assuntos
Contração Muscular , Músculo Esquelético , Masculino , Feminino , Humanos , Idoso , Músculo Esquelético/fisiologia , Contração Muscular/fisiologia , Neurônios Motores/fisiologia , Recrutamento Neurofisiológico/fisiologia , Eletromiografia , Contração Isométrica/fisiologia
9.
J Exp Med ; 221(5)2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38517332

RESUMO

Heterozygous mutations in the TBK1 gene can cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The majority of TBK1-ALS/FTD patients carry deleterious loss-of-expression mutations, and it is still unclear which TBK1 function leads to neurodegeneration. We investigated the impact of the pathogenic TBK1 missense variant p.E696K, which does not abolish protein expression, but leads to a selective loss of TBK1 binding to the autophagy adaptor protein and TBK1 substrate optineurin. Using organelle-specific proteomics, we found that in a knock-in mouse model and human iPSC-derived motor neurons, the p.E696K mutation causes presymptomatic onset of autophagolysosomal dysfunction in neurons precipitating the accumulation of damaged lysosomes. This is followed by a progressive, age-dependent motor neuron disease. Contrary to the phenotype of mice with full Tbk1 knock-out, RIPK/TNF-α-dependent hepatic, neuronal necroptosis, and overt autoinflammation were not detected. Our in vivo results indicate autophagolysosomal dysfunction as a trigger for neurodegeneration and a promising therapeutic target in TBK1-ALS/FTD.


Assuntos
Esclerose Amiotrófica Lateral , Demência Frontotemporal , Humanos , Camundongos , Animais , Esclerose Amiotrófica Lateral/patologia , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Doenças Neuroinflamatórias , Neurônios Motores/patologia , Fosforilação , Mutação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo
10.
Scand J Med Sci Sports ; 34(3): e14591, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38429941

RESUMO

The enigmatic benefits of acute limb ischemic preconditioning (IP) in enhancing muscle force and exercise performance have intrigued researchers. This study sought to unravel the underlying mechanisms, focusing on increased neural drive and the role of spinal excitability while excluding peripheral factors. Soleus Hoffmann (H)-reflex /M-wave recruitment curves and unpotentiated supramaximal responses were recorded before and after IP or a low-pressure control intervention. Subsequently, the twitch interpolation technique was applied during maximal voluntary contractions to assess conventional parameters of neural output. Following IP, there was an increase in both maximum normalized force and voluntary activation (VA) for the plantar flexor group, with negligible peripheral alterations. Greater benefits were observed in participants with lower VA levels. Despite greater H-reflex gains, soleus volitional (V)-wave and sEMG amplitudes remained unchanged. In conclusion, IP improves muscle force via enhanced neural drive to the muscles. This effect appears associated, at least in part, to reduced presynaptic inhibition and/or increased motoneuron excitability. Furthermore, the magnitude of the benefit is inversely proportional to the skeletal muscle's functional reserve, making it particularly noticeable in under-recruited muscles. These findings have implications for the strategic application of the IP procedure across diverse populations.


Assuntos
Precondicionamento Isquêmico , Músculo Esquelético , Masculino , Humanos , Eletromiografia/métodos , Músculo Esquelético/fisiologia , Contração Muscular/fisiologia , Neurônios Motores/fisiologia , Contração Isométrica/fisiologia , Reflexo H/fisiologia , Estimulação Elétrica
11.
Pol J Vet Sci ; 27(1): 75-84, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38511605

RESUMO

The trapezius muscle (TRAP) belongs to the scapulothoracic group of muscles, which play a crucial role in the integrity and strength of the upper limb, trunk, head, and neck movements and, thus, in maintaining balance. Combined retrograde tracing (using fluorescent tracer Fast Blue, FB) and double-labelling immunohistochemistry were applied to investigate the chemical coding of motoneurons projecting to the porcine TRAP. FB-positive (FB+) motoneurons supplying the cervical (c-TRAP) and thoracic part (th-TRAP) of the right (injected with the tracer) TRAP were located within the IX-th Rexed lamina in the ipsilateral ventral horn of the grey matter of the spinal medulla. Immunohistochemistry revealed that nearly all the neurons were cholinergic in nature [choline acetyltransferase (CHAT)- or vesicular acetylcholine transporter (VACHT)-positive]. Many retrogradelly labelled neurons displayed also immunoreactivity to calcitonin gene-related peptide (CGRP; approximately 68% of FB+ neurons). The smaller number of nerve cells (5%, 3%, 2% or 1%, respectively) stained for nitric oxide synthase (n-NOS), vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY) and substance P (SP). The retrogradely labelled neurons were closely apposed by nerve fibres expressing immunoreactivity to CHAT, VACHT, CGRP, SP, DßH, VIP, n-NOS, NPY, GAL, Leu-Enk and Met-Enk. Taking into account the clinical relevance of TRAP, the present results may be useful in designing further research aimed at the management of various dysfunctions of the muscle.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Músculos Superficiais do Dorso , Suínos , Animais , Neurônios Motores , Peptídeo Intestinal Vasoativo
12.
Nat Commun ; 15(1): 2189, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38467605

RESUMO

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. To identify additional genetic factors, we analyzed exome sequences in a large cohort of Chinese ALS patients and found a homozygous variant (p.L700P) in PCDHA9 in three unrelated patients. We generated Pcdhα9 mutant mice harboring either orthologous point mutation or deletion mutation. These mice develop progressive spinal motor loss, muscle atrophy, and structural/functional abnormalities of the neuromuscular junction, leading to paralysis and early lethality. TDP-43 pathology is detected in the spinal motor neurons of aged mutant mice. Mechanistically, we demonstrate that Pcdha9 mutation causes aberrant activation of FAK and PYK2 in aging spinal cord, and dramatically reduced NKA-α1 expression in motor neurons. Our single nucleus multi-omics analysis reveals disturbed signaling involved in cell adhesion, ion transport, synapse organization, and neuronal survival in aged mutant mice. Together, our results present PCDHA9 as a potential ALS gene and provide insights into its pathogenesis.


Assuntos
Esclerose Amiotrófica Lateral , Doenças Neurodegenerativas , Humanos , Camundongos , Animais , Idoso , Esclerose Amiotrófica Lateral/metabolismo , Doenças Neurodegenerativas/metabolismo , Camundongos Transgênicos , Neurônios Motores/metabolismo , Medula Espinal/metabolismo
13.
Cell Rep ; 43(2): 113801, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38363678

RESUMO

Axotomized spinal motoneurons (MNs) lose presynaptic inputs following peripheral nerve injury; however, the cellular mechanisms that lead to this form of synapse loss are currently unknown. Here, we delineate a critical role for neuronal kinase dual leucine zipper kinase (DLK)/MAP3K12, which becomes activated in axotomized neurons. Studies with conditional knockout mice indicate that DLK signaling activation in injured MNs triggers the induction of phagocytic microglia and synapse loss. Aspects of the DLK-regulated response include expression of C1q first from the axotomized MN and then later in surrounding microglia, which subsequently phagocytose presynaptic components of upstream synapses. Pharmacological ablation of microglia inhibits the loss of cholinergic C boutons from axotomized MNs. Together, the observations implicate a neuronal mechanism, governed by the DLK, in the induction of inflammation and the removal of synapses.


Assuntos
Neurônios Motores , Sinapses , Animais , Camundongos , Transdução de Sinais , Ativação do Complemento , Terminações Pré-Sinápticas , Camundongos Knockout
14.
Curr Biol ; 34(4): 910-915.e2, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38307023

RESUMO

Rhythmic locomotor activity, such as flying, swimming, or walking, results from an interplay between higher-order centers in the central nervous system, which initiate, maintain, and modify task-specific motor activity, downstream central pattern-generating neural circuits (CPGs) that can generate a default rhythmic motor output, and, finally, feedback from sense organs that modify basic motor activity toward functionality.1,2,3 In this context, CPGs provide phasic synaptic drive to motor neurons (MNs) and thereby support the generation of rhythmic activity for locomotion. We analyzed the synaptic drive that the leg MNs supplying the three main leg joints receive from CPGs in pharmacologically activated and deafferented preparations of the stick insect (Carausius morosus). We show that premotor CPGs pattern the tonic activity of five of the six leg MN pools by phasic inhibitory synaptic drive. These are the antagonistic MN pools supplying the thoraco-coxal joint and the femur-tibial joint4,5 and the levator MN pool supplying the coxa-trochanteral (CTr) joint. In contrast, rhythmic activity of the depressor MN pool supplying the CTr joint was found to be primarily based on a phasic excitatory drive. This difference is likely related to the pivotal role of the depressor muscle in generating leg stance during any walking situation. Thus, our results provide evidence for qualitatively differing mechanisms to generate rhythmic activity between MN pools in the same locomotor system.


Assuntos
Insetos , Caminhada , Animais , Insetos/fisiologia , Caminhada/fisiologia , Locomoção/fisiologia , Neurônios Motores/fisiologia
15.
Cell Rep Med ; 5(2): 101413, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38325382

RESUMO

Toxic signaling by extrasynaptic NMDA receptors (eNMDARs) is considered an important promoter of amyotrophic lateral sclerosis (ALS) disease progression. To exploit this therapeutically, we take advantage of TwinF interface (TI) inhibition, a pharmacological principle that, contrary to classical NMDAR pharmacology, allows selective elimination of eNMDAR-mediated toxicity via disruption of the NMDAR/TRPM4 death signaling complex while sparing the vital physiological functions of synaptic NMDARs. Post-disease onset treatment of the SOD1G93A ALS mouse model with FP802, a modified TI inhibitor with a safe pharmacology profile, stops the progressive loss of motor neurons in the spinal cord, resulting in a reduction in the serum biomarker neurofilament light chain, improved motor performance, and an extension of life expectancy. FP802 also effectively blocks NMDA-induced death of neurons in ALS patient-derived forebrain organoids. These results establish eNMDAR toxicity as a key player in ALS pathogenesis. TI inhibitors may provide an effective treatment option for ALS patients.


Assuntos
Esclerose Amiotrófica Lateral , Canais de Cátion TRPM , Camundongos , Animais , Humanos , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/patologia , Superóxido Dismutase/metabolismo , Superóxido Dismutase/farmacologia , Superóxido Dismutase/uso terapêutico , Camundongos Transgênicos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Modelos Animais de Doenças , Progressão da Doença
16.
Cell Rep Med ; 5(2): 101423, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38382464

RESUMO

Excitotoxicity-induced cell death in motor neurons is a major therapeutic target for amyotrophic lateral sclerosis (ALS). Yan et al.1 present a novel compound to specifically disrupt extra-synaptic NMDAR complexes, extending the lifespan of the SOD1G93A ALS mouse and ameliorating cell death.


Assuntos
Esclerose Amiotrófica Lateral , Camundongos , Animais , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Camundongos Transgênicos , Superóxido Dismutase/metabolismo , Neurônios Motores/metabolismo
17.
Nat Commun ; 15(1): 1546, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38413604

RESUMO

A fundamental question in neurodevelopmental biology is how flexibly the nervous system changes during development. To address this, we reconstructed the chemical connectome of dauer, an alternative developmental stage of nematodes with distinct behavioral characteristics, by volumetric reconstruction and automated synapse detection using deep learning. With the basic architecture of the nervous system preserved, structural changes in neurons, large or small, were closely associated with connectivity changes, which in turn evoked dauer-specific behaviors such as nictation. Graph theoretical analyses revealed significant dauer-specific rewiring of sensory neuron connectivity and increased clustering within motor neurons in the dauer connectome. We suggest that the nervous system in the nematode has evolved to respond to harsh environments by developing a quantitatively and qualitatively differentiated connectome.


Assuntos
Conectoma , Nematoides , Animais , Caenorhabditis elegans/fisiologia , Sinapses , Neurônios Motores
19.
Biomed Tech (Berl) ; 69(1): 49-59, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38354212

RESUMO

OBJECTIVES: Dysfunction of the central nervous system may inflict spastic movement disorder (SMD). Electrical stimuli were identified as promising therapeutic option. Electrical stimulation provided by a 58-electrode full body garment was investigated based on data from regular trial fittings. METHODS: Data from 72 testees were investigated. Age averages 36.6 (19.8) ys with 44 females. The cohort spans infantile cerebral paresis (CP) (n=29), multiple sclerosis (MS) (n=23) and stroke (n=20). Data were stratified by etiology and an entry BBS Score<45. RESULTS: Effect sizes (Cohen`s d) related BBS, TUG, FGA, 10mWT, WMFT, EQ5D5L and Pain. Significance levels are indicated by *: p<0.05, **: p<0.01, ***: p<0.001, (t): p<0.1: CP: 1.64***, 0.29*, 1.59***, 0.76(t), 1.00***, 0.5*, 1.28***; MS: 1.83***, 0.83***, 1.28**, 1.07***, 0.93*, 1,11**, 0.78*; Stroke: 1.28**, 0.78**, 0.89, 0.92**, 0.71, 1.26*, 0.78*. CONCLUSIONS: Multi-site transcutaneous electrical stimulation may increase ambulation related skills in subjects with SMD stemming from CP, MS and stroke. The results indicate effects on static and dynamic balance, fall risk, mobility, upper extremity improvement and an overall increase in health utility and a reduction in spasticity related pain. Effects are immediate as well as sustained. These results may inspire individual trial fittings and inform further controlled trials.


Assuntos
Paralisia Cerebral , Terapia por Estimulação Elétrica , Esclerose Múltipla , Acidente Vascular Cerebral , Feminino , Humanos , Paralisia Cerebral/terapia , Paralisia Cerebral/complicações , Paralisia Cerebral/diagnóstico , Esclerose Múltipla/terapia , Esclerose Múltipla/complicações , Neurônios Motores , Espasticidade Muscular/terapia , Terapia por Estimulação Elétrica/métodos , Dor/complicações , Vestuário
20.
Cells ; 13(3)2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38334639

RESUMO

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, for which current treatment options are limited. Recent studies have shed light on the role of mitochondria in ALS pathogenesis, making them an attractive therapeutic intervention target. This review contains a very comprehensive critical description of the involvement of mitochondria and mitochondria-mediated mechanisms in ALS. The review covers several key areas related to mitochondria in ALS, including impaired mitochondrial function, mitochondrial bioenergetics, reactive oxygen species, metabolic processes and energy metabolism, mitochondrial dynamics, turnover, autophagy and mitophagy, impaired mitochondrial transport, and apoptosis. This review also highlights preclinical and clinical studies that have investigated various mitochondria-targeted therapies for ALS treatment. These include strategies to improve mitochondrial function, such as the use of dichloroacetate, ketogenic and high-fat diets, acetyl-carnitine, and mitochondria-targeted antioxidants. Additionally, antiapoptotic agents, like the mPTP-targeting agents minocycline and rasagiline, are discussed. The paper aims to contribute to the identification of effective mitochondria-targeted therapies for ALS treatment by synthesizing the current understanding of the role of mitochondria in ALS pathogenesis and reviewing potential convergent therapeutic interventions. The complex interplay between mitochondria and the pathogenic mechanisms of ALS holds promise for the development of novel treatment strategies to combat this devastating disease.


Assuntos
Esclerose Amiotrófica Lateral , Doenças Neurodegenerativas , Humanos , Esclerose Amiotrófica Lateral/metabolismo , Doenças Neurodegenerativas/metabolismo , Mitocôndrias/metabolismo , Neurônios Motores/patologia , Apoptose
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