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1.
Biochemistry (Mosc) ; 89(Suppl 1): S34-S56, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38621743

RESUMO

Mutations that disrupt the function of the DNA/RNA-binding protein FUS could cause amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. One of the key features in ALS pathogenesis is the formation of insoluble protein aggregates containing aberrant isoforms of the FUS protein in the cytoplasm of upper and lower motor neurons. Reproduction of human pathology in animal models is the main tool for studying FUS-associated pathology and searching for potential therapeutic agents for ALS treatment. In this review, we provide a systematic analysis of the role of FUS protein in ALS pathogenesis and an overview of the results of modelling FUS-proteinopathy in animals.


Assuntos
Esclerose Amiotrófica Lateral , Animais , Humanos , Esclerose Amiotrófica Lateral/genética , Proteína FUS de Ligação a RNA/genética , Proteína FUS de Ligação a RNA/metabolismo , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Citoplasma/metabolismo , Mutação , Modelos Animais de Doenças
2.
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 , Animais , Humanos , Camundongos , Esclerose Amiotrófica Lateral/patologia , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Neurônios Motores/patologia , Mutação , Doenças Neuroinflamatórias , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo
3.
AJNR Am J Neuroradiol ; 45(4): 494-503, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38548305

RESUMO

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving rapid motor neuron degeneration leading to brain, primarily precentral, atrophy. Neurofilament light chains are a robust prognostic biomarker highly specific to ALS, yet associations between neurofilament light chains and MR imaging outcomes are not well-understood. We investigated the role of neurofilament light chains as mediators among neuroradiologic assessments, precentral neurodegeneration, and disability in ALS. MATERIALS AND METHODS: We retrospectively analyzed a prospective cohort of 29 patients with ALS (mean age, 56 [SD, 12] years; 18 men) and 36 controls (mean age, 49 [SD, 11] years; 18 men). Patients underwent 3T (n = 19) or 7T (n = 10) MR imaging, serum (n = 23) and CSF (n = 15) neurofilament light chains, and clinical (n = 29) and electrophysiologic (n = 27) assessments. The control group had equivalent 3T (n = 25) or 7T (n = 11) MR imaging. Two trained neuroradiologists performed blinded qualitative assessments of MR imaging anomalies (n = 29 patients, n = 36 controls). Associations between precentral cortical thickness and neurofilament light chains and clinical and electrophysiologic data were analyzed. RESULTS: We observed extensive cortical thinning in patients compared with controls. MR imaging analyses showed significant associations between precentral cortical thickness and bulbar or arm impairment following distributions corresponding to the motor homunculus. Finally, uncorrected results showed positive interactions among precentral cortical thickness, serum neurofilament light chains, and electrophysiologic outcomes. Qualitative MR imaging anomalies including global atrophy (P = .003) and FLAIR corticospinal tract hypersignal anomalies (P = .033), correlated positively with serum neurofilament light chains. CONCLUSIONS: Serum neurofilament light chains may be an important mediator between clinical symptoms and neuronal loss according to cortical thickness. Furthermore, MR imaging anomalies might have underestimated prognostic value because they seem to indicate higher serum neurofilament light chain levels.


Assuntos
Esclerose Amiotrófica Lateral , Doenças Neurodegenerativas , Masculino , Humanos , Pessoa de Meia-Idade , Esclerose Amiotrófica Lateral/diagnóstico por imagem , Estudos Retrospectivos , Estudos Prospectivos , Filamentos Intermediários , Neurônios Motores/patologia , Imageamento por Ressonância Magnética/métodos , Atrofia/patologia
4.
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
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.
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
8.
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
9.
Muscle Nerve ; 69(4): 477-489, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38305586

RESUMO

INTRODUCTION/AIMS: Genetics is an important risk factor for amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons. Recent findings demonstrate that in addition to specific genetic mutations, structural variants caused by genetic instability can also play a causative role in ALS. Genomic instability can lead to deletions, duplications, insertions, inversions, and translocations in the genome, and these changes can sometimes lead to fusion of distinct genes into a single transcript. Gene fusion events have been studied extensively in cancer; however, they have not been thoroughly investigated in ALS. The aim of this study was to determine whether gene fusions are present in ALS. METHODS: Gene fusions were identified using STAR Fusion v1.10.0 software in bulk RNA-Seq data from human postmortem samples from publicly available data sets from Target ALS and the New York Genome Center ALS Consortium. RESULTS: We report the presence of gene fusion events in several brain regions as well as in spinal cord samples in ALS. Although most gene fusions were intra-chromosomal events between neighboring genes and present in both ALS and control samples, there was a significantly greater number of unique gene fusions in ALS compared to controls. Lastly, we identified specific gene fusions with a significant burden in ALS, that were absent from both control samples and known cancer gene fusion databases. DISCUSSION: Collectively, our findings reveal an enrichment of gene fusions in ALS and suggest that these events may be an additional genetic cause linked to ALS pathogenesis.


Assuntos
Esclerose Amiotrófica Lateral , Doenças Neurodegenerativas , Humanos , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Neurônios Motores/patologia , Fusão Gênica
10.
Nature ; 625(7994): 345-351, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38057661

RESUMO

Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated with motor disorders1. The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins2. In the majority of cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes3,4. The presence of amyloid filaments and their identities and structures in the remaining approximately 10% of FTLD cases are unknown but are widely believed to be composed of the protein fused in sarcoma (FUS, also known as translocated in liposarcoma). As such, these cases are commonly referred to as FTLD-FUS. Here we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Surprisingly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15, also known as TATA-binding protein-associated factor 2N) rather than of FUS itself. The filament fold is formed from residues 7-99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, both showing upper and lower motor neuron pathology. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.


Assuntos
Degeneração Lobar Frontotemporal , Fatores Associados à Proteína de Ligação a TATA , Humanos , Amiloide/química , Amiloide/metabolismo , Amiloide/ultraestrutura , Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Microscopia Crioeletrônica , Demência Frontotemporal/etiologia , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Degeneração Lobar Frontotemporal/complicações , Degeneração Lobar Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Córtex Motor/metabolismo , Córtex Motor/patologia , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Fatores Associados à Proteína de Ligação a TATA/química , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Fatores Associados à Proteína de Ligação a TATA/ultraestrutura , Lobo Temporal/metabolismo , Lobo Temporal/patologia
11.
Acta Neurol Belg ; 124(1): 25-36, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37704780

RESUMO

Stroke is the third leading cause of death and disability worldwide. Post-stroke spasticity (PSS) is the most common complication of stroke but represents only one of the many manifestations of upper motor neuron syndrome. As an upper motor neuron, the corticospinal tract (CST) is the only direct descending motor pathway that innervates the spinal motor neurons and is closely related to the recovery of limb function in patients with PSS. Therefore, promoting axonal remodeling in the CST may help identify new therapeutic strategies for PSS. In this review, we outline the pathological mechanisms of PSS, specifically their relationship with CST, and therapeutic strategies for axonal regeneration of the CST after stroke. We found it to be closely associated with astroglial scarring produced by astrocyte activation and its secretion of neurotrophic factors, mainly after the onset of cerebral ischemia. We hope that this review offers insight into the relationship between CST and PSS and provides a basis for further studies.


Assuntos
Tratos Piramidais , Acidente Vascular Cerebral , Humanos , Tratos Piramidais/patologia , Axônios/patologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/patologia , Neurônios Motores/patologia , Recuperação de Função Fisiológica/fisiologia
12.
Cells ; 12(23)2023 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-38067180

RESUMO

Amyotrophic lateral sclerosis (ALS) is a motor neuron (MN) disease associated with progressive muscle atrophy, paralysis, and eventually death. Growing evidence demonstrates that the pathological process leading to ALS is the result of multiple altered mechanisms occurring not only in MNs but also in other cell types inside and outside the central nervous system. In this context, the involvement of skeletal muscle has been the subject of a few studies on patients and ALS animal models. In this work, by using primary myocytes derived from the ALS transgenic hSOD1(G93A) mouse model, we observed that the myogenic capability of such cells was defective compared to cells derived from control mice expressing the nonpathogenic hSOD1(WT) isoform. The correct in vitro myogenesis of hSOD1(G93A) primary skeletal muscle cells was rescued by the addition of a conditioned medium from healthy hSOD1(WT) myocytes, suggesting the existence of an in trans activity of secreted factors. To define a dataset of molecules participating in such safeguard action, we conducted comparative metabolomic profiling of a culture medium collected from hSOD1(G93A) and hSOD1(WT) primary myocytes and report here an altered secretion of amino acids and lipid-based signaling molecules. These findings support the urgency of better understanding the role of the skeletal muscle secretome in the regulation of the myogenic program and mechanisms of ALS pathogenesis and progression.


Assuntos
Esclerose Amiotrófica Lateral , Doença dos Neurônios Motores , Camundongos , Humanos , Animais , Esclerose Amiotrófica Lateral/metabolismo , Neurônios Motores/patologia , Camundongos Transgênicos , Superóxido Dismutase-1/metabolismo , Doença dos Neurônios Motores/metabolismo , Células Musculares/metabolismo , Metaboloma
13.
Signal Transduct Target Ther ; 8(1): 451, 2023 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-38086800

RESUMO

Amyotrophic lateral sclerosis (ALS) is a devastating fatal neurodegenerative disease with no cure. Receptor-interacting protein kinase 1 (RIPK1) has been proposed to mediate pathogenesis of ALS. Primidone has been identified as an old drug that can also inhibit RIPK1 kinase. We conducted a drug-repurposing biomarker study of primidone as a RIPK1 inhibitor using SOD1G93A mice and ALS patients. SOD1G93A mice treated with primidone showed significant delay of symptomatic onset and improved motor performance. One-hundred-sixty-two ALS participants dosed daily with primidone (62.5 mg) completed 24-week follow-up. A significant reduction was showed in serum levels of RIPK1 and IL-8, which were significantly higher in ALS patients than that of healthy controls (P < 0.0001). Serum RIPK1 levels were correlated positively with the severity of bulbar symptoms (P < 0.05). Our study suggests that serum levels of RIPK1 and IL-8 in peripheral can be used as clinical biomarkers for the activation of RIPK1 in central nervous system in human ALS patients. Repurposing primidone may provide a promising therapeutic strategy for ALS. The effect of primidone for the treatment of other inflammatory diseases may also be considered, since the activation of RIPK1 has been implicated in mediating a variety of inflammatory diseases including COVID-19-associated cytokine release syndrome (CRS). (ChiCTR2200060149).


Assuntos
Esclerose Amiotrófica Lateral , Doenças Neurodegenerativas , Animais , Humanos , Camundongos , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Biomarcadores , Interleucina-8/genética , Camundongos Transgênicos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Doenças Neurodegenerativas/metabolismo , Primidona/metabolismo , Primidona/farmacologia , Primidona/uso terapêutico , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/farmacologia , Superóxido Dismutase/metabolismo , Superóxido Dismutase/farmacologia , Superóxido Dismutase/uso terapêutico , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Superóxido Dismutase-1/farmacologia
14.
Cell Mol Biol (Noisy-le-grand) ; 69(10): 1-8, 2023 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-37953591

RESUMO

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most common motoneuron diseases affecting adults and infants, respectively. ALS and SMA are both characterized by the selective degeneration of motoneurons. Although different in their genetic etiology, growing evidence indicates that they share molecular and cellular pathogenic signatures that constitute potential common therapeutic targets. We previously described a motoneuron-specific death pathway elicited by the Fas death receptor, whereby vulnerable ALS motoneurons show an exacerbated sensitivity to Fas activation. However, the mechanisms that drive the loss of SMA motoneurons remains poorly understood. Here, we describe an in vitro model of SMA-associated degeneration using primary motoneurons derived from Smn2B/- SMA mice and show that Fas activation selectively triggers death of the proximal motoneurons. Fas-induced death of SMA motoneurons has the molecular signature of the motoneuron-selective Fas death pathway that requires activation of p38 kinase, caspase-8, -9 and -3 as well as upregulation of collapsin response mediator protein 4 (CRMP4). In addition, Rho-associated Kinase (ROCK) is required for Fas recruitment. Remarkably, we found that exogenous activation of Fas also promotes axonal elongation in both wildtype and SMA motoneurons. Axon outgrowth of motoneurons promoted by Fas requires the activity of ERK, ROCK and caspases. This work defines a dual role of Fas signaling in motoneurons that can elicit distinct responses from cell death to axonal growth.


Assuntos
Esclerose Amiotrófica Lateral , Atrofia Muscular Espinal , Humanos , Camundongos , Animais , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Camundongos Transgênicos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patologia , Axônios/patologia
15.
Zhonghua Yi Xue Za Zhi ; 103(39): 3071-3076, 2023 Oct 24.
Artigo em Chinês | MEDLINE | ID: mdl-37840177

RESUMO

Amyotrophic lateral sclerosis(ALS) is a progressive and fatal neurodegenerative disease that mainly involves upper and lower motor neurons. It lacks clear biomarkers and can be clearly diagnosed only one and a half years after the onset. Gene test is of great significance for diagnosis, prognosis and genetic counseling. In recent years, several gene therapy studies have entered the clinical trial stage of ALS, among which the antisense oligonucleotide therapy targeting the pathogenic variation of the superoxide dismutase 1 (SOD1) gene has been launched, and it is urgent to carry out routine gene test in clinical practice. On the basis of progress of ALS gene research in recent years, family history, age of onset and typical clinical manifestations of patients are no longer considered as the basis for genetic testing. However, the target genes of clinical gene testing needs to be further clarified according to the diagnostic purpose, the testing method and scheme need to be standardized, and the genetic consultation before testing should be paid attention to, and the informed consent should be fully achieved.


Assuntos
Esclerose Amiotrófica Lateral , Doenças Neurodegenerativas , Humanos , Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Neurônios Motores/patologia , Superóxido Dismutase-1/genética , Testes Genéticos , Mutação , Superóxido Dismutase/genética
16.
Mol Neurodegener ; 18(1): 75, 2023 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-37858176

RESUMO

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, resulting in muscle weakness, atrophy, paralysis, and eventually death. Motor cortical hyperexcitability is a common phenomenon observed at the presymptomatic stage of ALS. Both cell-autonomous (the intrinsic properties of motor neurons) and non-cell-autonomous mechanisms (cells other than motor neurons) are believed to contribute to cortical hyperexcitability. Decoding the pathological relevance of these dynamic changes in motor neurons and glial cells has remained a major challenge. This review summarizes the evidence of cortical hyperexcitability from both clinical and preclinical research, as well as the underlying mechanisms. We discuss the potential role of glial cells, particularly microglia, in regulating abnormal neuronal activity during the disease progression. Identifying early changes such as neuronal hyperexcitability in the motor system may provide new insights for earlier diagnosis of ALS and reveal novel targets to halt the disease progression.


Assuntos
Esclerose Amiotrófica Lateral , Humanos , Esclerose Amiotrófica Lateral/patologia , Neurônios Motores/patologia , Neuroglia/patologia , Microglia/patologia , Progressão da Doença
17.
Cells ; 12(20)2023 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-37887320

RESUMO

C9orf72 mutations are the most common form of familial amyotrophic lateral sclerosis (C9-ALS). It causes the production of proline-arginine dipeptide repeat proteins (PR-DPRs) in motor neurons (MNs), leading to the molecular pathology characteristic of ALS. UNC13A is critical for maintaining the synaptic function of MNs. Most ALS patients have nuclear deletion of the splicing repressor TDP-43 in MNs, which causes inclusion of the cryptic exon (CE) of UNC13A mRNA, resulting in nonsense-mediated mRNA decay and reduced protein expression. Therefore, in this study, we explored the role of PR-DPR in CE inclusion of UNC13A mRNA. Our results showed that PR-DPR (PR50) induced CE inclusion and decreased the protein expression of UNC13A in human neuronal cell lines. We also identified an interaction between the RNA-binding protein NOVA1 and PR50 by yeast two-hybrid screening. NOVA1 expression is known to be reduced in patients with ALS. We found that knockdown of NOVA1 enhanced CE inclusion of UNC13A mRNA. Furthermore, the naturally occurring triterpene betulin can inhibit the interaction between NOVA1 and PR50, thus preventing CE inclusion of UNC13A mRNA and protein reduction in human neuronal cell lines. This study linked PR-DPR with CE inclusion of UNC13A mRNA and developed candidate therapeutic strategies for C9-ALS using betulin.


Assuntos
Esclerose Amiotrófica Lateral , Humanos , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Arginina/metabolismo , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Dipeptídeos/metabolismo , Neurônios Motores/patologia , Antígeno Neuro-Oncológico Ventral , Prolina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
18.
Neuropeptides ; 102: 102386, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37856900

RESUMO

Amyotrophic lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of motor neurons in the central nervous system. Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) account for approximately in 20% of familial ALS cases. The pathological mechanisms underlying the toxicity induced by mutated SOD1 are still unknown. However, it has been hypothesized that oxidative stress (OS) has a crucial role in motor neuron degeneration in ALS patients. Moreover, it has been described that SOD1 mutation interferes expression of nuclear factor erythroid 2-related factor 2 (Nrf2), a protective key modulator against OS and reactive oxygen species (ROS) formation. The protective effect of pituitary adenylate cyclase-activating peptide (PACAP) has been demonstrated in various neurological disorders, including ALS. Some of its effects are mediated by the stimulation of an intracellular factor known as activity-dependent protein (ADNP). The role of PACAP-ADNP axis on mutated SOD1 motor neuron degeneration has not been explored, yet. The present study aimed to investigate whether PACAP prevented apoptotic cell death induced by growth factor deprivation through ADNP activation and whether the peptidergic axis can counteract the OS insult. By using an in vitro model of ALS, we demonstrated that PACAP by binding to PAC1 receptor (PAC1R) prevented motor neuron death induced by serum deprivation through induction of the ADNP expression via PKC stimulation. Furthermore, we have also demonstrated that the PACAP/ADNP axis counteracted ROS formation by inducing translocation of the Nfr2 from the cytoplasm to the nucleus. In conclusion, our study provides new insights regarding the protective role of PACAP-ADNP in ALS.


Assuntos
Esclerose Amiotrófica Lateral , Doenças Neurodegenerativas , Fármacos Neuroprotetores , Humanos , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/metabolismo , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Superóxido Dismutase-1/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Mutação , Proteínas do Tecido Nervoso/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/farmacologia
19.
Artigo em Russo | MEDLINE | ID: mdl-37796077

RESUMO

Motor neuron diseases (MND) include two main forms - amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). A certain part of these diseases is hereditary, while etiology of sporadic cases remains unknown. Both entities are known to develop because of motoneurons damage. Difference between them lies in the state of the descending pyramidal pathways. The pyramidal pathways in SMA are intact, as brain pyramidal neurons are not affected, thus pathology of SMA is restricted to anterior horns of spinal cord. Meanwhile, most forms of ALS arise due to loss of both cerebral and spinal motoneurons, which, in addition to anterior horn lesion, leads to pyramidal descending pathways damage either in brain or in spinal cord. While pathological distinction between these two entities is clear and definite, the clinical difference remains obscure. We present the case of 41-year old patient with MND, in whom spinal MR tractography has revealed lateral columns to be intact that proves the utility of spinal MR tractography in differential diagnosis between ALS and SMA. Given that ischemic diseases of the spinal cord often occur with a clinical picture of MND, we also examined this patient using spinal MRI angiography, revealing a pronounced narrowing and tortuosity of the spinal arteries, complicated by occlusion of the right twelve intercostal artery.


Assuntos
Esclerose Amiotrófica Lateral , Doença dos Neurônios Motores , Atrofia Muscular Espinal , Adulto , Humanos , Esclerose Amiotrófica Lateral/patologia , Angiografia por Ressonância Magnética , Doença dos Neurônios Motores/diagnóstico por imagem , Neurônios Motores/patologia , Medula Espinal/diagnóstico por imagem
20.
Int J Mol Sci ; 24(19)2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37834374

RESUMO

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, characterized in its typical presentation by a combination of lower and upper motor neuron symptoms, with a progressive course and fatal outcome. Due to increased recognition of the non-motor symptoms, it is currently considered a multisystem disorder with great heterogeneity, regarding genetical, clinical, and neuropathological features. Often underestimated, autonomic signs and symptoms have been described in patients with ALS, and various method analyses have been used to assess autonomic nervous system involvement. The aim of this paper is to offer a narrative literature review on autonomic disturbances in ALS, based on the scarce data available to date.


Assuntos
Esclerose Amiotrófica Lateral , Doenças Neurodegenerativas , Disautonomias Primárias , Humanos , Esclerose Amiotrófica Lateral/patologia , Doenças Neurodegenerativas/patologia , Neurônios Motores/patologia , Disautonomias Primárias/etiologia , Disautonomias Primárias/patologia
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