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1.
PLoS One ; 15(1): e0228109, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31978144

RESUMO

Irradiation of food at 50-55 kGy results in a profound, chronic demyelinating-remyelinating disease of the entire central nervous system (CNS) in cats, named Feline Irradiated Diet-Induced Demyelination (FIDID). This study examines the early stages of demyelination and long-term consequences of demyelination and remyelination on axon survival or loss. Myelin vacuolation is the primary defect leading to myelin breakdown, demyelination then prompt remyelination in the spinal cord and brain. There is no evidence of oligodendrocyte death. The spinal cord dorsal column is initially spared yet eventually becomes severely demyelinated with subsequent loss of axons in the core and then surface of the fasciculus gracilis. However remyelination of the sub-pial axons in the dorsal column results in their protection. While there was a lack of biochemical evidence of Vitamin B12 deficiency, the pathological similarities of FIDID with sub-acute combined degeneration (SCD) led us to explore treatment with Vitamin B12. Treatment led to recovery or improvement in some cats and neurologic relapse on cessation of B12 therapy. While the reason that irradiated food is myelinotoxic in the cat remains unresolved, nonetheless the neuropathological changes match exactly what is seen in SCD and its models and provide an ideal model to study the cellular and molecular basis of remyelination.


Assuntos
Doenças Desmielinizantes/patologia , Dieta , Degeneração Neural/patologia , Radiação , Doença Aguda , Animais , Axônios/patologia , Gatos , Doença Crônica , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/fisiopatologia , Modelos Animais de Doenças , Feminino , Macrófagos/patologia , Masculino , Metaboloma , Microglia/patologia , Bainha de Mielina/metabolismo , Degeneração Neural/sangue , Degeneração Neural/fisiopatologia , Neuropatologia , Remielinização , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Fatores de Tempo , Vitamina B 12/sangue
2.
Nat Med ; 26(1): 118-130, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31873312

RESUMO

Gene silencing with virally delivered shRNA represents a promising approach for treatment of inherited neurodegenerative disorders. In the present study we develop a subpial technique, which we show in adult animals successfully delivers adeno-associated virus (AAV) throughout the cervical, thoracic and lumbar spinal cord, as well as brain motor centers. One-time injection at cervical and lumbar levels just before disease onset in mice expressing a familial amyotrophic lateral sclerosis (ALS)-causing mutant SOD1 produces long-term suppression of motoneuron disease, including near-complete preservation of spinal α-motoneurons and muscle innervation. Treatment after disease onset potently blocks progression of disease and further α-motoneuron degeneration. A single subpial AAV9 injection in adult pigs or non-human primates using a newly designed device produces homogeneous delivery throughout the cervical spinal cord white and gray matter and brain motor centers. Thus, spinal subpial delivery in adult animals is highly effective for AAV-mediated gene delivery throughout the spinal cord and supraspinal motor centers.


Assuntos
Esclerose Amiotrófica Lateral/terapia , Dependovirus/metabolismo , Inativação Gênica , Técnicas de Transferência de Genes , Neurônios Motores/patologia , Degeneração Neural/terapia , Pia-Máter/patologia , Medula Espinal/patologia , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/fisiopatologia , Animais , Atrofia , Progressão da Doença , Potencial Evocado Motor , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação/patologia , Interneurônios/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Desenvolvimento Muscular , Degeneração Neural/genética , Degeneração Neural/fisiopatologia , Pia-Máter/fisiopatologia , Primatas , Dobramento de Proteína , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/administração & dosagem , Medula Espinal/diagnóstico por imagem , Medula Espinal/fisiopatologia , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Suínos
3.
Invest Ophthalmol Vis Sci ; 60(14): 4606-4618, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31756254

RESUMO

Purpose: To investigate the neuroprotective effects of Lycium barbarum polysaccharides (LBP) against chronic ocular hypertension (OHT) in rats and to consider if effects differed when treatment was applied before (pretreatment) or during (posttreatment) chronic IOP elevation. Methods: Sprague-Dawley rats (10-weeks old) underwent suture implantation around the limbus for 15 weeks (OHT) or 1 day (sham). Four experimental groups were studied, three OHT groups (n = 8 each) treated either with vehicle (PBS), LBP pretreatment or posttreatment, and a sham control (n = 5) received no treatment. LBP (1 mg/kg) pre- and posttreatment were commenced at 1 week before and 4 weeks after OHT induction, respectively. Treatments continued up through week 15. IOP was monitored twice weekly for 15 weeks. Optical coherence tomography and ERG were measured at baseline, week 4, 8, 12, and 15. Eyes were collected for ganglion cell layer (GCL) histologic analysis at week 15. Results: Suture implantation successfully induced approximately 50% IOP elevation and the cumulative IOP was similar between the three OHT groups. When compared with vehicle control (week 4: -23 ± 5%, P = 0.03), LBP pretreatment delayed the onset of retinal nerve fiber layer (RNFL) thinning (week 4, 8: -2 ± 7%, -11 ± 3%, P > 0.05) and arrested further reduction up through week 15 (-10 ± 4%, P > 0.05). LBP posttreatment intervention showed no significant change in rate of loss (week 4, 15: -25 ± 4.1%, -28 ± 3%). However, both LBP treatments preserved the retinal ganglion cells (RGC) and retinal functions up to week 15, which were significantly reduced in vehicle control. Conclusions: LBP posttreatment arrested the subsequent neuronal degeneration after treatment commencement and preserved RGC density and retinal functions in a chronic OHT model, which was comparable with pretreatment outcomes.


Assuntos
Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Degeneração Neural/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Hipertensão Ocular/tratamento farmacológico , Animais , Doença Crônica , Eletrorretinografia , Feminino , Pressão Intraocular/fisiologia , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Fibras Nervosas/patologia , Hipertensão Ocular/metabolismo , Hipertensão Ocular/fisiopatologia , Ratos , Ratos Sprague-Dawley , Retina/fisiopatologia , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica
4.
Neuron ; 104(5): 856-868.e5, 2019 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-31623919

RESUMO

Neurodegenerative diseases appear to progress by spreading via brain connections. Here we evaluated this transneuronal degeneration hypothesis by attempting to predict future atrophy in a longitudinal cohort of patients with behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA). We determined patient-specific "epicenters" at baseline, located each patient's epicenters in the healthy functional connectome, and derived two region-wise graph theoretical metrics to predict future atrophy: (1) shortest path length to the epicenter and (2) nodal hazard, the cumulative atrophy of a region's first-degree neighbors. Using these predictors and baseline atrophy, we could accurately predict longitudinal atrophy in most patients. The regions most vulnerable to subsequent atrophy were functionally connected to the epicenter and had intermediate levels of baseline atrophy. These findings provide novel, longitudinal evidence that neurodegeneration progresses along connectional pathways and, further developed, could lead to network-based clinical tools for prognostication and disease monitoring.


Assuntos
Encéfalo/patologia , Demência Frontotemporal/patologia , Modelos Neurológicos , Degeneração Neural/patologia , Vias Neurais/patologia , Idoso , Atrofia/patologia , Atrofia/fisiopatologia , Encéfalo/fisiopatologia , Feminino , Demência Frontotemporal/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Degeneração Neural/fisiopatologia , Vias Neurais/fisiopatologia
5.
Nat Neurosci ; 22(11): 1793-1805, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31591561

RESUMO

Neuromuscular junction (NMJ) disruption is an early pathogenic event in amyotrophic lateral sclerosis (ALS). Yet, direct links between NMJ pathways and ALS-associated genes such as FUS, whose heterozygous mutations cause aggressive forms of ALS, remain elusive. In a knock-in Fus-ALS mouse model, we identified postsynaptic NMJ defects in newborn homozygous mutants that were attributable to mutant FUS toxicity in skeletal muscle. Adult heterozygous knock-in mice displayed smaller neuromuscular endplates that denervated before motor neuron loss, which is consistent with 'dying-back' neuronopathy. FUS was enriched in subsynaptic myonuclei, and this innervation-dependent enrichment was distorted in FUS-ALS. Mechanistically, FUS collaborates with the ETS transcription factor ERM to stimulate transcription of acetylcholine receptor genes. Co-cultures of induced pluripotent stem cell-derived motor neurons and myotubes from patients with FUS-ALS revealed endplate maturation defects due to intrinsic FUS toxicity in both motor neurons and myotubes. Thus, FUS regulates acetylcholine receptor gene expression in subsynaptic myonuclei, and muscle-intrinsic toxicity of ALS mutant FUS may contribute to dying-back motor neuronopathy.


Assuntos
Esclerose Amiotrófica Lateral/fisiopatologia , Regulação da Expressão Gênica/fisiologia , Degeneração Neural/fisiopatologia , Junção Neuromuscular/metabolismo , Proteína FUS de Ligação a RNA/fisiologia , Adulto , Esclerose Amiotrófica Lateral/patologia , Animais , Células Cultivadas , Feminino , Técnicas de Introdução de Genes , Humanos , Masculino , Camundongos , Camundongos Knockout , Neurônios Motores/patologia , Fibras Musculares Esqueléticas/patologia , Junção Neuromuscular/patologia , Proteína FUS de Ligação a RNA/genética , Proteína FUS de Ligação a RNA/metabolismo , Receptores Colinérgicos/metabolismo , Adulto Jovem
6.
J Hum Genet ; 64(11): 1145-1151, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31515523

RESUMO

More than 80 known or suspected genes/loci have been reported to be involved in hereditary spastic paraplegia (HSP). Genetic and clinical overlap have been reported between HSP and other neurological condition, yet about 50% of HSP patients remain genetically undiagnosed. To identify novel genes involved in HSP, we performed a genetic analysis of 383 HSP patients from 289 families with HSP. Two patients with biallelic SPTAN1 variants were identified; one carried the c.2572G>T p.(Ala858Ser) and c.4283C>G p.(Ala1428Gly) variants, and the second also carried the c.2572G>T p.(Ala858Ser) variant, and an additional variant, c.6990G>C p.(Met2330Ile). In silico predictive and structural analyses suggested that these variants are likely to be deleterious. SPTAN1 was highly intolerant for functional variants (in the top 0.31% of intolerant genes) with much lower observed vs. expected number of loss-of-function variants (8 vs. 142.7, p < 5 × 10-15). Using public databases of animal models and previously published data, we have found previously described zebrafish, mouse, and rat animal models of SPTAN1 deficiency, all consistently showing axonal degeneration, fitting the pathological features of HSP in humans. This study expands the phenotype of SPTAN1 mutations, which at the heterozygous state, when occurred de novo, may cause early infantile epileptic encephalopathy-5 (EIEE5). Our results further suggest that SPTAN1 may cause autosomal recessive HSP, and that it should be included in genetic screening panels for genetically undiagnosed HSP patients.


Assuntos
Proteínas de Transporte/genética , Proteínas dos Microfilamentos/genética , Degeneração Neural/genética , Paraplegia Espástica Hereditária/genética , Animais , Axônios/patologia , Proteínas de Transporte/química , Simulação por Computador , Feminino , Heterozigoto , Humanos , Masculino , Camundongos , Proteínas dos Microfilamentos/química , Modelos Animais , Mutação/genética , Degeneração Neural/fisiopatologia , Fenótipo , Conformação Proteica , Paraplegia Espástica Hereditária/epidemiologia , Peixe-Zebra/genética
7.
Annu Rev Neurosci ; 42: 107-127, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31283900

RESUMO

Maturation of neuronal circuits requires selective elimination of synaptic connections. Although neuron-intrinsic mechanisms are important in this process, it is increasingly recognized that glial cells also play a critical role. Without proper functioning of these cells, the number, morphology, and function of synaptic contacts are profoundly altered, resulting in abnormal connectivity and behavioral abnormalities. In addition to their role in synaptic refinement, glial cells have also been implicated in pathological synapse loss and dysfunction following injury or nervous system degeneration in adults. Although mechanisms regulating glia-mediated synaptic elimination are still being uncovered, it is clear this complex process involves many cues that promote and inhibit the removal of specific synaptic connections. Gaining a greater understanding of these signals and the contribution of different cell types will not only provide insight into this critical biological event but also be instrumental in advancing knowledge of brain development and neural disease.


Assuntos
Sistema Nervoso Central/embriologia , Degeneração Neural/fisiopatologia , Doenças do Sistema Nervoso/fisiopatologia , Neuroglia/fisiologia , Neurônios/fisiologia , Sistema Nervoso Periférico/embriologia , Sinapses/fisiologia , Animais , Astrócitos/fisiologia , Evolução Biológica , Sistema Nervoso Central/crescimento & desenvolvimento , Sinais (Psicologia) , Exossomos/fisiologia , Humanos , Invertebrados/embriologia , Microglia/fisiologia , Morfogênese , Bainha de Mielina/fisiologia , Junção Neuromuscular/embriologia , Sistema Nervoso Periférico/crescimento & desenvolvimento , Sinapses/patologia
8.
Nat Neurosci ; 22(7): 1089-1098, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31235908

RESUMO

Pericytes are positioned between brain capillary endothelial cells, astrocytes and neurons. They degenerate in multiple neurological disorders. However, their role in the pathogenesis of these disorders remains debatable. Here we generate an inducible pericyte-specific Cre line and cross pericyte-specific Cre mice with iDTR mice carrying Cre-dependent human diphtheria toxin receptor. After pericyte ablation with diphtheria toxin, mice showed acute blood-brain barrier breakdown, severe loss of blood flow, and a rapid neuron loss that was associated with loss of pericyte-derived pleiotrophin (PTN), a neurotrophic growth factor. Intracerebroventricular PTN infusions prevented neuron loss in pericyte-ablated mice despite persistent circulatory changes. Silencing of pericyte-derived Ptn rendered neurons vulnerable to ischemic and excitotoxic injury. Our data demonstrate a rapid neurodegeneration cascade that links pericyte loss to acute circulatory collapse and loss of PTN neurotrophic support. These findings may have implications for the pathogenesis and treatment of neurological disorders that are associated with pericyte loss and/or neurovascular dysfunction.


Assuntos
Proteínas de Transporte/fisiologia , Citocinas/fisiologia , Degeneração Neural/fisiopatologia , Proteínas do Tecido Nervoso/fisiologia , Neurônios/patologia , Pericitos/fisiologia , Choque/fisiopatologia , Animais , Isquemia Encefálica/fisiopatologia , Capilares/fisiopatologia , Proteínas de Transporte/uso terapêutico , Células Cultivadas , Circulação Cerebrovascular/fisiologia , Citocinas/deficiência , Citocinas/uso terapêutico , Células Endoteliais/citologia , Feminino , Genes Reporter , Infusões Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Degeneração Neural/tratamento farmacológico , Neuroglia/metabolismo , Neurônios/metabolismo , Neurotoxinas/toxicidade , Regiões Promotoras Genéticas , Proteínas Recombinantes de Fusão/metabolismo , Choque/metabolismo , Choque/patologia
9.
Physiol Rep ; 7(9): e14072, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31050222

RESUMO

Evidence suggests that adult stem cell types and progenitor cells act collectively in a given tissue to maintain and heal organs, such as muscle, through a release of a multitude of molecules packaged into exosomes from the different cell types. Using this principle for the development of bioinspired therapeutics that induces homeostatic renormalization, here we show that the collection of molecules released from four cell types, including mesenchymal stem cells, fibroblast, neural stem cells, and astrocytes, rescues degenerating neurons and cells. Specifically, oxidative stress induced in a human recombinant TDP-43- or FUS-tGFP U2OS cell line by exposure to sodium arsenite was shown to be significantly reduced by our collection of molecules using in vitro imaging of FUS and TDP-43 stress granules. Furthermore, we also show that the collective secretome rescues cortical neurons from glutamate toxicity as evidenced by increased neurite outgrowth, reduced LDH release, and reduced caspase 3/7 activity. These data are the first in a series supporting the development of stem cell-based exosome systems therapeutics that uses a physiological renormalization strategy to treat neurodegenerative diseases.


Assuntos
Meios de Cultivo Condicionados/farmacologia , Degeneração Neural/fisiopatologia , Regeneração Nervosa/efeitos dos fármacos , Células-Tronco/metabolismo , Animais , Arsenitos , Astrócitos/metabolismo , Caspase 3/metabolismo , Caspase 7/metabolismo , Células Cultivadas , Exossomos/metabolismo , Fibroblastos/metabolismo , Ácido Glutâmico , Humanos , L-Lactato Desidrogenase/metabolismo , Células-Tronco Mesenquimais/metabolismo , Degeneração Neural/patologia , Células-Tronco Neurais/metabolismo , Neuritos/efeitos dos fármacos , Neuritos/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos
10.
Science ; 364(6435): 89-93, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30948552

RESUMO

Paralysis occurring in amyotrophic lateral sclerosis (ALS) results from denervation of skeletal muscle as a consequence of motor neuron degeneration. Interactions between motor neurons and glia contribute to motor neuron loss, but the spatiotemporal ordering of molecular events that drive these processes in intact spinal tissue remains poorly understood. Here, we use spatial transcriptomics to obtain gene expression measurements of mouse spinal cords over the course of disease, as well as of postmortem tissue from ALS patients, to characterize the underlying molecular mechanisms in ALS. We identify pathway dynamics, distinguish regional differences between microglia and astrocyte populations at early time points, and discern perturbations in several transcriptional pathways shared between murine models of ALS and human postmortem spinal cords.


Assuntos
Esclerose Amiotrófica Lateral/genética , Expressão Gênica , Neurônios Motores/metabolismo , Medula Espinal/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Camundongos , Microglia/metabolismo , Microglia/patologia , Neurônios Motores/patologia , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Degeneração Neural/genética , Degeneração Neural/fisiopatologia , Neuroglia/metabolismo , Neuroglia/patologia , Mudanças Depois da Morte , Análise Espaço-Temporal , Medula Espinal/patologia , Transcriptoma
11.
EMBO Mol Med ; 11(5)2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30940675

RESUMO

Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine-mediated neuromuscular disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. While transcriptional dysregulation is known to play a critical role in the pathogenesis of SBMA, the underlying molecular pathomechanisms remain unclear. DNA methylation is a fundamental epigenetic modification that silences the transcription of various genes that have a CpG-rich promoter. Here, we showed that DNA methyltransferase 1 (Dnmt1) is highly expressed in the spinal motor neurons of an SBMA mouse model and in patients with SBMA. Both genetic Dnmt1 depletion and treatment with RG108, a DNA methylation inhibitor, ameliorated the viability of SBMA model cells. Furthermore, a continuous intracerebroventricular injection of RG108 mitigated the phenotype of SBMA mice. DNA methylation array analysis identified hairy and enhancer of split 5 (Hes5) as having a CpG island with hyper-methylation in the promoter region, and the Hes5 expression was strongly silenced in SBMA. Moreover, Hes5 over-expression rescued the SBMA cells possibly by inducing Smad2 phosphorylation. Our findings suggest DNA hyper-methylation underlies the neurodegeneration in SBMA.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Metilação de DNA , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Peptídeos/toxicidade , Ftalimidas/farmacologia , Proteínas Repressoras/metabolismo , Triptofano/análogos & derivados , Idoso , Animais , Sobrevivência Celular/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Modelos Biológicos , Atividade Motora/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/enzimologia , Neurônios Motores/patologia , Atrofia Muscular Espinal/patologia , Degeneração Neural/fisiopatologia , Regiões Promotoras Genéticas/genética , Receptores Androgênicos/metabolismo , Proteína Smad2/metabolismo , Medula Espinal/patologia , Triptofano/farmacologia
12.
Glia ; 67(8): 1542-1557, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31025779

RESUMO

Parkinson's disease (PD) is characterized by the selective degeneration of dopamine (DA) neurons of the substantia nigra pars compacta (SN), while the neighboring ventral tegmental area (VTA) is relatively spared. The mechanisms underlying this selectivity are not fully understood. Here, we demonstrate a vital role for subregional astrocytes in the protection of VTA DA neurons. We found that elimination of astrocytes in vitro exposes a novel vulnerability of presumably protected VTA DA neurons to the PD mimetic toxin MPP+ , as well as exacerbation of SN DA neuron vulnerability. Conversely, VTA astrocytes protected both VTA and SN DA neurons from MPP+ toxicity in a dose dependent manner, and this protection was mediated via a secreted molecule. RNAseq analysis of isolated VTA and SN astrocytes demonstrated a vast array of transcriptional differences between these two closely related populations demonstrating regional heterogeneity of midbrain astrocytes. We found that GDF15, a member of the TGFß superfamily which is expressed 230-fold higher in VTA astrocytes than SN, recapitulates neuroprotection of both rat midbrain and iPSC-derived DA neurons, whereas its knockdown conversely diminished this effect. Neuroprotection was likely mediated through the GRFAL receptor expressed on DA neurons. Together; these results suggest that subregional differences in astrocytes underlie the selective degeneration or protection of DA neurons in PD.


Assuntos
Astrócitos/fisiologia , Degeneração Neural/fisiopatologia , Neuroproteção/fisiologia , Transtornos Parkinsonianos/fisiopatologia , Animais , Células Cultivadas , Técnicas de Cocultura , Neurônios Dopaminérgicos/fisiologia , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Fator 15 de Diferenciação de Crescimento/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Parte Compacta da Substância Negra/fisiopatologia , Ratos Transgênicos , Área Tegmentar Ventral/fisiopatologia
13.
Hum Brain Mapp ; 40(12): 3464-3474, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31020731

RESUMO

Amyotrophic lateral sclerosis (ALS) is a progressive and intractable neurodegenerative disease of human motor system characterized by progressive muscular weakness and atrophy. A considerable body of research has demonstrated significant structural and functional abnormalities of the primary motor cortex in patients with ALS. In contrast, much less attention has been paid to the abnormalities of cerebellum in this disease. Using multimodal magnetic resonance imagining data of 60 patients with ALS and 60 healthy controls, we examined changes in gray matter volume (GMV), white matter (WM) fractional anisotropy (FA), and functional connectivity (FC) in patients with ALS. Compared with healthy controls, patients with ALS showed decreased GMV in the left precentral gyrus and increased GMV in bilateral cerebellum, decreased FA in the left corticospinal tract and body of corpus callosum, and decreased FC in multiple brain regions, involving bilateral postcentral gyrus, precentral gyrus and cerebellum anterior lobe, among others. Meanwhile, we found significant intermodal correlations among GMV of left precentral gyrus, FA of altered WM tracts, and FC of left precentral gyrus, and that WM microstructural alterations seem to play important roles in mediating the relationship between GMV and FC of the precentral gyrus, as well as the relationship between GMVs of the precentral gyrus and cerebellum. These findings provided evidence for the precentral degeneration and cerebellar compensation in ALS, and the involvement of WM alterations in mediating the relationship between pathologies of the primary motor cortex and cerebellum, which may contribute to a better understanding of the pathophysiology of ALS.


Assuntos
Esclerose Amiotrófica Lateral/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Imagem de Tensor de Difusão/métodos , Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Adulto , Idoso , Esclerose Amiotrófica Lateral/fisiopatologia , Cerebelo/fisiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Degeneração Neural/diagnóstico por imagem , Degeneração Neural/fisiopatologia , Adulto Jovem
14.
Turk Neurosurg ; 29(3): 434-439, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984987

RESUMO

AIM: To examine ischemic neurodegeneration of the ciliospinal center on permanent miosis following subarachnoid hemorrhage (SAH). MATERIAL AND METHODS: Nineteen rabbits were examined in this study. The animals were divided into three groups, as control (GI, n=5), sham (GII, n=5) and study group (GIII, n=9). Pupil diameters were measured after giving 0.5 mL physiological saline for sham and autologous arterial blood for the study group into the cervico-thoracic subarachnoid space. After three weeks of follow up, the cervico-thoracic cord and bilateral superior cervical sympathetic ganglia were removed. The pupil diameter values were compared with degenerated neuron volumes of sympathetic ganglia and degenerated neuron densities of thoracic sympathetic nuclei which were studied by stereological methods. RESULTS: The mean pupil diameter was 5180 ± 370 µm and the mean degenerated neuron density of the ciliospinal center was 4 ± 1/mm3 in animals of the control group (GI). These values were 9850 ± 610 εm, 10 ± 3/mm3 in sham (GII), and 7.010 ± 440 εm and 98 ± 21/mm3 in the study (GIII) groups. There was an inverse relationship between degenerated neuron density of the ciliospinal nuclei and pupil diameters. CONCLUSION: We showed and reported for the first time that ciliospinal sympathetic center ischemia-induced neurodegeneration may have been responsible for permanent miosis following SAH.


Assuntos
Isquemia/diagnóstico , Miose/diagnóstico , Hemorragia Subaracnóidea/diagnóstico , Gânglio Cervical Superior/patologia , Animais , Modelos Animais de Doenças , Isquemia/complicações , Isquemia/fisiopatologia , Masculino , Miose/etiologia , Miose/fisiopatologia , Degeneração Neural/diagnóstico , Degeneração Neural/etiologia , Degeneração Neural/fisiopatologia , Pupila/fisiologia , Coelhos , Distribuição Aleatória , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/fisiopatologia , Gânglio Cervical Superior/fisiopatologia
15.
Neurología (Barc., Ed. impr.) ; 34(3): 143-152, abr. 2019. graf
Artigo em Espanhol | IBECS | ID: ibc-180779

RESUMO

Introducción: La enfermedad de Parkinson) es un desorden neurodegenerativo caracterizado por problemas de equilibro, rigidez muscular y lentitud para realizar movimiento, debido a la pérdida de neuronas dopaminérgicas de la sustancia nigra pars compacta (SNpc) y la reducción de los niveles de dopamina. Se sabe que el sistema endocannabinoide modula el funcionamiento de la vía nigroestriatal, a través de ligandos endógenos como anandamida (AEA), que es hidrolizado por la hidrolasa amida de ácidos grasos (FAAH). El objetivo de este trabajo consiste en aumentar los niveles de AEA, a través de la inhibición de FAAH por URB-597 y evaluar la modulación que ejerce AEA en la muerte neuronal dopaminérgica inducida por 1-metil-4-fenil-1,2,3,6-tetrahidropiridina (MPTP). Métodos: Se incluyeron 4 grupos experimentales con una n = 6, el primero fue el grupo control sin tratamiento, un grupo al cual se le administró (0,2 mg/kg) URB-597 cada 3.er día durante 30 días, un grupo tratado con MPTP (30mg/kg) por 5 días y un grupo inyectado con URB-597 + MPTP. Tres días después de la última administración de los grupos experimentales, se llevó a cabo la aplicación de los siguientes paradigmas conductuales: prueba de la barra vertical, barra inclinada y longitud de la zancada para comparar la coordinación motriz. Posteriormente, se analizó la inmunorreactividad de las células dopaminérgicas y de microglía en SNpc y cuerpo estriado (CE). Resultados: Los resultados muestran que el grupo tratado con URB-597 previo a la administración de MPTP, presentó un mejor desempeño en la realización de las pruebas conductuales comparados con los ratones que recibieron la administración de MPTP. Los hallazgos del análisis inmunohistoquímico de las células dopaminérgicas muestran que el grupo tratado con MPTP presenta una disminución en el número de células y fibras dopaminérgicas tanto en la SNpc y CE. En los animales tratados con URB-597 previo a la administración de MPTP se observó un aumento en la inmunorreactividad de tirosina hidroxilasa en comparación al grupo tratado con MPTP. Con respecto a la inmunorreactividad de las células de microglía, el grupo tratado con MPTP presentó una mayor inmunorreactividad a Iba-1 en el CE y la SNpc comparado con el grupo tratado con URB-597 previo a la administración de MPTP. Conclusión: Los resultados obtenidos muestran que el URB-597 genera un efecto protector, al inhibir la muerte neuronal dopaminérgica, y disminución en la inmunorreactividad microglial y una mejora en las alteraciones motoras causadas por MPTP


Introduction: Parkinson's disease (PD) is a neurodegenerative disorder characterised by balance problems, muscle rigidity, and slow movement due to low dopamine levels and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The endocannabinoid system is known to modulate the nigrostriatal pathway through endogenous ligands such as anandamide (AEA), which is hydrolysed by fatty acid amide hydrolase (FAAH). The purpose of this study was to increase AEA levels using FAAH inhibitor URB597 to evaluate the modulatory effect of AEA on dopaminergic neuronal death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Methods: Our study included 4 experimental groups (n = 6 mice per group): a control group receiving no treatment, a group receiving URB597 (0.2 mg/kg) every 3 days for 30 days, a group treated with MPTP (30 mg/kg) for 5 days, and a group receiving URB597 and subsequently MPTP injections. Three days after the last dose, we conducted a series of behavioural tests (beam test, pole test, and stride length test) to compare motor coordination between groups. We subsequently analysed immunoreactivity of dopaminergic cells and microglia in the SNpc and striatum. Results: Mice treated with URB597 plus MPTP were found to perform better on behavioural tests than mice receiving MPTP only. According to the immunohistochemistry study, mice receiving MPTP showed fewer dopaminergic cells and fibres in the SNpc and striatum. Animals treated with URB597 plus MPTP displayed increased tyrosine hydroxylase immunoreactivity compared to those treated with MPTP only. Regarding microglial immunoreactivity, the group receiving MPTP showed higher Iba1 immunoreactivity in the striatum and SNpc than did the group treated with URB597 plus MPTP. Conclusion: Our results show that URB597 exerts a protective effect since it inhibits dopaminergic neuronal death, decreases microglial immunoreactivity, and improves MPTP-induced motor alterations


Assuntos
Camundongos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Degeneração Neural/tratamento farmacológico , Ácidos Graxos/antagonistas & inibidores , Amidoidrolases/metabolismo , Neurônios Dopaminérgicos , Doença de Parkinson/fisiopatologia , Degeneração Neural/fisiopatologia , Intoxicação por MPTP/tratamento farmacológico , Endocanabinoides , Modelos Animais de Doenças , Microglia , Estudos de Casos e Controles , Fármacos Neuroprotetores/farmacocinética
16.
Annu Rev Neurosci ; 42: 149-168, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-30883261

RESUMO

Glia are abundant components of animal nervous systems. Recognized 170 years ago, concerted attempts to understand these cells began only recently. From these investigations glia, once considered passive filler material in the brain, have emerged as active players in neuron development and activity. Glia are essential for nervous system function, and their disruption leads to disease. The nematode Caenorhabditis elegans possesses glial types similar to vertebrate glia, based on molecular, morphological, and functional criteria, and has become a powerful model in which to study glia and their neuronal interactions. Facile genetic and transgenic methods in this animal allow the discovery of genes required for glial functions, and effects of glia at single synapses can be monitored by tracking neuron shape, physiology, or animal behavior. Here, we review recent progress in understanding glia-neuron interactions in C. elegans. We highlight similarities with glia in other animals, and suggest conserved emerging principles of glial function.


Assuntos
Caenorhabditis elegans/citologia , Neuroglia/fisiologia , Neurônios/fisiologia , Envelhecimento/fisiologia , Animais , Animais Geneticamente Modificados , Orientação de Axônios , Caenorhabditis elegans/fisiologia , Proteínas de Transporte/fisiologia , Comunicação Celular , Canais Iônicos/fisiologia , Degeneração Neural/fisiopatologia , Terminações Nervosas/fisiologia , Terminações Nervosas/ultraestrutura , Proteínas do Tecido Nervoso/fisiologia , Neurogênese , Plasticidade Neuronal , Neurópilo/fisiologia , Neurotransmissores/fisiologia , Sono/fisiologia , Especificidade da Espécie , Transmissão Sináptica , Vertebrados/embriologia , Vertebrados/fisiologia
17.
Cells ; 8(3)2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30901919

RESUMO

Nicotinamide mononucleotide adenylyltransferase (NMNAT), a key enzyme for NAD⁺ synthesis, is well known for its activity in neuronal survival and attenuation of Wallerian degeneration. Recent investigations in invertebrate models have, however, revealed that NMNAT activity negatively impacts upon axon regeneration. Overexpression of Nmnat in laser-severed Drosophila sensory neurons reduced axon regeneration, while axon regeneration was enhanced in injured mechanosensory axons in C. elegans nmat-2 null mutants. These diametrically opposite effects of NMNAT orthologues on neuroprotection and axon regeneration appear counterintuitive as there are many examples of neuroprotective factors that also promote neurite outgrowth, and enhanced neuronal survival would logically facilitate regeneration. We suggest here that while NMNAT activity and NAD⁺ production activate neuroprotective mechanisms such as SIRT1-mediated deacetylation, the same mechanisms may also activate a key axonal regeneration inhibitor, namely phosphatase and tensin homolog (PTEN). SIRT1 is known to deacetylate and activate PTEN which could, in turn, suppress PI3 kinase⁻mTORC1-mediated induction of localized axonal protein translation, an important process that determines successful regeneration. Strategic tuning of Nmnat activity and NAD⁺ production in axotomized neurons may thus be necessary to promote initial survival without inhibiting subsequent regeneration.


Assuntos
Axônios/patologia , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Regeneração Nervosa , Nicotinamida-Nucleotídeo Adenililtransferase/metabolismo , Animais , Morte Celular , Neuroproteção
18.
Dev Neurobiol ; 79(5): 479-496, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30912256

RESUMO

In Hydra the nervous system is composed of neurons and mechanosensory cells that differentiate from interstitial stem cells (ISCs), which also provide gland cells and germ cells. The adult nervous system is actively maintained through continuous de novo neurogenesis that occurs at two distinct paces, slow in intact animals and fast in regenerating ones. Surprisingly Hydra vulgaris survive the elimination of cycling interstitial cells and the subsequent loss of neurogenesis if force-fed. By contrast, H. oligactis animals exposed to cold temperature undergo gametogenesis and a concomitant progressive loss of neurogenesis. In the cold-sensitive strain Ho_CS, this loss irreversibly leads to aging and animal death. Within four weeks, Ho_CS animals lose their contractility, feeding response, and reaction to light. Meanwhile, two positive regulators of neurogenesis, the homeoprotein prdl-a and the neuropeptide Hym-355, are no longer expressed, while the "old" RFamide-expressing neurons persist. A comparative transcriptomic analysis performed in cold-sensitive and cold-resistant strains confirms the downregulation of classical neuronal markers during aging but also shows the upregulation of putative regulators of neurotransmission and neurogenesis such as AHR, FGFR, FoxJ3, Fral2, Jagged, Meis1, Notch, Otx1, and TCF15. The switch of Fral2 expression from neurons to germ cells suggests that in aging animals, the neurogenic program active in ISCs is re-routed to germ cells, preventing de novo neurogenesis and impacting animal survival.


Assuntos
Envelhecimento/fisiologia , Hydra/fisiologia , Neurogênese/fisiologia , Envelhecimento/patologia , Animais , Temperatura Baixa , Ingestão de Alimentos/fisiologia , Expressão Gênica , Hydra/citologia , Movimento/fisiologia , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Neurônios/citologia , Neurônios/patologia , Neurônios/fisiologia , Células-Tronco/citologia , Células-Tronco/patologia , Células-Tronco/fisiologia
19.
World Neurosurg ; 125: e972-e977, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30763747

RESUMO

OBJECTIVE: We created a neck trauma model by injecting blood into the sheath of rabbits' carotid bodies (CBs). Then we determined the relationship between neuronal degeneration of the CB due to hemorrhage of this organ and its clinical effects such as blood pH and heart rhythm. METHODS: The present study included 24 adult male New Zealand rabbits. The animals were divided into 3 groups: control (n = 5); sham (0.5 mL saline injected into CBs; n = 5); and study (CB trauma model; n = 14). pH values and heart rhythms were recorded before the experiment to determine the values under normal conditions, and measurements were repeated thrice in the days following the experiment. The number of normal and degenerated neuron density of CBs was counted. The relationship between the blood pH values, heart rhythms, and degenerated neuron densities was analyzed. RESULTS: Heart rhythms were 218 ± 20 in the control group, 197 ± 16 in the sham group (P = 0.09), and 167 ± 13 in the study group (P < 0.0005). pH values were 7.40 ± 0.041 in the control group, 7.321 ± 0.062 in the sham group (P = 0.203), and 7.23 ± 0.02 in study group (P < 0.0005). Degenerated neuron densities were 12 ± 4/mm3 in the control group, 430 ± 74/mm3 in the sham group (P < 0.005), and 7434 ± 810/mm3 in the study group (P < 0.0001). CONCLUSIONS: A high degenerate neuron density in the CB can decrease blood pH and hearth rhythm after neck trauma, and there might be a close relationship between the number of degenerated neurons and clinical findings (such as heart rhythm and blood pH). This relationship suggests that injury to the glossopharyngeal nerve-CB network can cause acidosis by disturbing the breathing-circulating reflex and results in respiratory acidosis.


Assuntos
Acidose/etiologia , Corpo Carotídeo/fisiopatologia , Traumatismos do Nervo Glossofaríngeo/etiologia , Lesões do Pescoço/complicações , Degeneração Neural/etiologia , Animais , Traumatismos do Nervo Glossofaríngeo/fisiopatologia , Frequência Cardíaca/fisiologia , Concentração de Íons de Hidrogênio , Masculino , Lesões do Pescoço/fisiopatologia , Degeneração Neural/fisiopatologia , Coelhos
20.
Proc Natl Acad Sci U S A ; 116(8): 3316-3321, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30718430

RESUMO

Mind wandering represents the human capacity for internally focused thought and relies upon the brain's default network and its interactions with attentional networks. Studies have characterized mind wandering in healthy people, yet there is limited understanding of how this capacity is affected in clinical populations. This paper used a validated thought-sampling task to probe mind wandering capacity in two neurodegenerative disorders: behavioral variant frontotemporal dementia [(bvFTD); n = 35] and Alzheimer's disease [(AD); n = 24], compared with older controls (n = 37). These patient groups were selected due to canonical structural and functional changes across sites of the default and frontoparietal networks and well-defined impairments in cognitive processes that support mind wandering. Relative to the controls, bvFTD patients displayed significantly reduced mind wandering capacity, offset by a significant increase in stimulus-bound thought. In contrast, AD patients demonstrated comparable levels of mind wandering to controls, in the context of a relatively subtle shift toward stimulus-/task-related forms of thought. In the patient groups, mind wandering was associated with gray matter integrity in the hippocampus/parahippocampus, striatum, insula, and orbitofrontal cortex. Resting-state functional connectivity revealed associations between mind wandering capacity and connectivity within and between regions of the frontoparietal and default networks with distinct patterns evident in patients vs. controls. These findings support a relationship between altered mind wandering capacity in neurodegenerative disorders and structural and functional integrity of the default and frontoparietal networks. This paper highlights a dimension of cognitive dysfunction not well documented in neurodegenerative disorders and validates current models of mind wandering in a clinical population.


Assuntos
Doença de Alzheimer/fisiopatologia , Atrofia/fisiopatologia , Encefalopatias/fisiopatologia , Hipocampo/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Atrofia/diagnóstico por imagem , Atenção/fisiologia , Encefalopatias/diagnóstico por imagem , Mapeamento Encefálico , Feminino , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/fisiopatologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/fisiopatologia , Hipocampo/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Degeneração Neural/diagnóstico por imagem , Degeneração Neural/fisiopatologia , Rede Nervosa/fisiologia , Vias Neurais/fisiologia , Descanso/fisiologia , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/fisiopatologia
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