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2.
Nat Commun ; 11(1): 3848, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737286

RESUMO

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper and lower motor neurons (MNs). We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice. Being the retromer involved in trafficking of hydrolases, a pathological hallmark in ALS, we design, synthesize and characterize an array of retromer stabilizers based on bis-guanylhydrazones connected by a 1,3-phenyl ring linker. We select compound 2a as a potent and bioavailable interactor of VPS35-VPS29. Indeed, while increasing retromer stability in ALS mice, compound 2a attenuates locomotion impairment and increases MNs survival. Moreover, compound 2a increases VPS35 in iPSCs-derived MNs and shows brain bioavailability. Our results clearly suggest the retromer as a valuable druggable target in ALS.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Hidrazonas/farmacologia , Neurônios Motores/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas de Transporte Vesicular/genética , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Diferenciação Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Hidrazonas/síntese química , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Ligação Proteica/efeitos dos fármacos , Multimerização Proteica , Relação Estrutura-Atividade , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Proteínas de Transporte Vesicular/metabolismo
3.
Adv Exp Med Biol ; 1207: 53-74, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671738

RESUMO

Motor neuron diseases (MND) are a group of fatal progressive neurodegenerative diseases, which selectively affect the motor system in the anterior horn of spinal cord, brainstem, cortex and pyramidal tract. Motor neurons could be divided into two groups, which are upper groups in the motor cortex and lower groups in the brain stem and spinal cord. Loss of lower motor neurons leads to muscle weakness, wasting and cramps. Loss of upper motor neurons leads to brisk reflexes and functional limits. There are several types of motor neuron disease: amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP), progressive muscular atrophy (PMA), primary lateral sclerosis (PLS). Now, the studies of autophagy in MND focus on the type of ALS, so this chapter will summarize the alteration of autophagy in motor neurons, and how that knowledge contributes to our understanding of the pathogenesis of ALS.


Assuntos
Autofagia , Doença dos Neurônios Motores , Esclerose Amiotrófica Lateral , Humanos , Neurônios Motores , Medula Espinal
5.
PLoS One ; 15(6): e0233991, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497060

RESUMO

Neuropeptides are secreted molecules that have conserved roles modulating many processes, including mood, reproduction, and feeding. Dysregulation of neuropeptide signaling is also implicated in neurological disorders such as epilepsy. However, much is unknown about the mechanisms regulating specific neuropeptides to mediate behavior. Here, we report that the expression levels of dozens of neuropeptides are up-regulated in response to circuit activity imbalance in C. elegans. acr-2 encodes a homolog of human nicotinic receptors, and functions in the cholinergic motoneurons. A hyperactive mutation, acr-2(gf), causes an activity imbalance in the motor circuit. We performed cell-type specific transcriptomic analysis and identified genes differentially expressed in acr-2(gf), compared to wild type. The most over-represented class of genes are neuropeptides, with insulin-like-peptides (ILPs) the most affected. Moreover, up-regulation of neuropeptides occurs in motoneurons, as well as sensory neurons. In particular, the induced expression of the ILP ins-29 occurs in the BAG neurons, which were previously shown to function in gas-sensing. We also show that this up-regulation of ins-29 in acr-2(gf) animals is activity-dependent. Our genetic and molecular analyses support cooperative effects for ILPs and other neuropeptides in promoting motor circuit activity in the acr-2(gf) background. Together, this data reveals that a major transcriptional response to motor circuit dysregulation is in up-regulation of multiple neuropeptides, and suggests that BAG sensory neurons can respond to intrinsic activity states to feedback on the motor circuit.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Neuropeptídeos/genética , Receptores Nicotínicos/genética , Transcriptoma , Animais , Caenorhabditis elegans/fisiologia , Perfilação da Expressão Gênica , Neurônios Motores/metabolismo , Mutação , Células Receptoras Sensoriais/metabolismo
6.
PLoS One ; 15(6): e0233843, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497147

RESUMO

The vestibular system is essential to produce adequate postural responses enabling voluntary movement. However, how the vestibular system influences corticospinal output during postural tasks is still unknown. Here, we examined the modulation exerted by the vestibular system on corticospinal output during standing. Healthy subjects (n = 25) maintained quiet standing, head facing forward with eyes closed. Galvanic vestibular stimulation (GVS) was applied bipolarly and binaurally at different delays prior to transcranial magnetic stimulation (TMS) which triggered motor evoked potentials (MEPs). With the cathode right/anode left configuration, MEPs in right Soleus (SOL) muscle were significantly suppressed when GVS was applied at ISI = 40 and 130ms before TMS. With the anode right/cathode left configuration, no significant changes were observed. Changes in the MEP amplitude were then compared to changes in the ongoing EMG when GVS was applied alone. Only the decrease in MEP amplitude at ISI = 40ms occurred without change in the ongoing EMG, suggesting that modulation occurred at a premotoneuronal level. We further investigated whether vestibular modulation could occur at the motor cortex level by assessing changes in the direct corticospinal pathways using the short-latency facilitation of the SOL Hoffmann reflex (H-reflex) by TMS. None of the observed modulation occurred at the level of motor cortex. Finally, using the long-latency facilitation of the SOL H-reflex, we were able to confirm that the suppression of MEP at ISI = 40ms occurred at a premotoneuronal level. The data indicate that vestibular signals modulate corticospinal output to SOL at both premotoneuronal and motoneuronal levels during standing.


Assuntos
Eletromiografia/métodos , Tratos Piramidais/fisiologia , Posição Ortostática , Vestíbulo do Labirinto/fisiologia , Adulto , Potencial Evocado Motor/fisiologia , Feminino , Lateralidade Funcional/fisiologia , Reflexo H/fisiologia , Voluntários Saudáveis , Humanos , Masculino , Córtex Motor/fisiologia , Neurônios Motores/fisiologia , Músculo Esquelético/fisiologia , Estimulação Transcraniana por Corrente Contínua , Estimulação Magnética Transcraniana , Adulto Jovem
7.
West Afr J Med ; 37(3): 284-289, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32476124

RESUMO

Takayasu's arteritis (TA) is an idiopathic form of large vessel granulomatous vasculitis that mainly affects the aorta and its major branches, most frequently in young women under 50 years. While traditionally, it is a disease found commonly in Asia continent, it has also been reported from different parts of the world, albeit with a few reports from Sub-Sahara Africa. The clinical presentations are variable and are commonly from systemic inflammation, vascular occlusive diseases and aneurysm. Asymptomatic cases of TA have been documented and are usually discovered incidentally on physical examination. Common vascular symptoms from different series include vascular claudication, reduced or absent pulse, carotid bruit, hypertension and headache. Facial mononeuropathy and retinal ischaemic changes are rare findings in TA. However, occlusive disease of ulnar artery has not been reported in TA despite our extensive literature search. Here, we present a 48-year-old woman, who was admitted via the medical emergency with community acquired pneumonia but was incidentally diagnosed with Takayasu arteritis with lower motor neuron facial nerve palsy, unilateral blindness, and ulnar artery occlusion. Multidisciplinary management was instituted and patient was discharged after resolution of community acquired pneumonia, vascular claudication, and chronic headache. TA often presents asymptomatically and sometimes with atypical features and thus we suggest high index of suspicion and detailed cardio-vascular examination in young individuals with unexplained chronic headache, facial nerve palsy and visual symptoms.


Assuntos
Arteriopatias Oclusivas/diagnóstico , Cegueira/etiologia , Doenças do Nervo Facial/etiologia , Arterite de Takayasu/diagnóstico , Ulna/irrigação sanguínea , Infecções Comunitárias Adquiridas/diagnóstico , Feminino , Humanos , Achados Incidentais , Pessoa de Meia-Idade , Neurônios Motores , Pneumonia/diagnóstico
8.
J Oral Sci ; 62(3): 265-270, 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32493863

RESUMO

Orexins (Oxs) are multifunctional neuropeptides, secreted from the lateral hypothalamus, that stimulate feeding behavior and energy expenditure. In this study, the direct effects of Oxs on the membrane properties of trigeminal motoneurons (TMNs) were examined, which critically participate in the genesis of rhythmical oral motor activities underlying suckling and mastication. Sprague-Dawley rats (3-6 day-old) were used to obtain whole-cell patch-clamp recordings from TMNs. Bath application of Ox-A depolarized the membrane potential and induced inward current, wherein Na+ and Ca2+ were charge carriers. Transient receptor potential channel activation potentially contributed to current and voltage responses by way of Ox-A. Ox-A increased the peak amplitude and duration at half-amplitude of the medium-duration after hyperpolarization following the action potential. The interspike frequency of steady-state firings during repetitive discharge was increased, along with a shift in the frequency-current relationship occurring toward the left. Extracellular and intracellular Ca2+ were involved in regulating modulatory effects, but a requisite level of intracellular Ca2+ was not essential for Ox-induced upregulation of the interspike frequency. Ox-A also enhanced conditional bursting induced by N-methyl-d-aspartate and 5-HT, suggesting it participates in modulating TMNs' discharge patterns during various oral motor activities.


Assuntos
Neurônios Motores , Potenciais de Ação , Animais , Potenciais da Membrana , Orexinas , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley
9.
Neuron ; 106(5): 705-707, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32497504

RESUMO

Mutations in TANK-binding kinase 1 (TBK1) are linked to ALS-FTD. In this issue of Neuron, Gerbino et al. (2020) show how missense mutations in the kinase domain of TBK1 differentially affect disease onset and progression in an ALS mouse model.


Assuntos
Esclerose Amiotrófica Lateral , Animais , Progressão da Doença , Camundongos , Neurônios Motores , Proteínas Serina-Treonina Quinases , Superóxido Dismutase-1
10.
J Electromyogr Kinesiol ; 52: 102421, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32353708

RESUMO

This study included spike trigger averaging (STA) procedures to examine the acceptability of the Precision Decomposition (PD) III derived motor unit action potential (MUAP) trains that met the >90% accuracy criteria from the reconstruct-and-test. MUs met the >90% accuracy criteria from the reconstruct-and-test with STA procedures then applied. Y-intercepts and slopes were calculated for the firing rate- and MUAP amplitude-recruitment threshold relationships. Gaussian noise (1% of the SD of the mean interspike interval) was added to the firing times with the changes in MUAPs quantified. A total of 455 MUs were decomposed with 155 MUs removed as a result of the reconstruct-and-test. Five additional MUs were excluded via the STA criteria. The MUAP waveforms deteriorated with the inclusion of Gaussian noise. There were differences in the derived action potentials amplitudes of higher-threshold MUs between the PD III algorithm and the STA procedure. There was excellent agreement among the slopes and y-intercepts between the relationships that included or excluded MUs that did not meet the STA criteria. There was good agreement between the MUAP amplitude-recruitment threshold relationships derived from the PD III and STA procedure. The addition of the STA procedures did not alter the MU-derived relationships.


Assuntos
Potenciais de Ação , Neurônios Motores/fisiologia , Músculo Esquelético/fisiologia , Adulto , Eletromiografia/métodos , Eletromiografia/normas , Humanos , Masculino , Músculo Esquelético/inervação , Tempo de Reação , Reprodutibilidade dos Testes
11.
J Peripher Nerv Syst ; 25(2): 204-207, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32388880

RESUMO

Acute demyelinating inflammatory polyneuropathy (AIDP) is the most common type of Guillain-Barré syndrome (GBS) in Europe, following several viral and bacterial infections. Data on AIDP-patients associated with SARS-CoV-2 (coronavirus-2) infection are scarce. We describe the case of a 54-years-old Caucasian female patient with typical clinical and electrophysiological manifestations of AIDP, who was reported positive with PCR for SARS-CoV-2, 3 weeks prior to onset of the neurological symptoms. She did not experience a preceding fever or respiratory symptoms, but a transient loss of smell and taste. At the admission to our neurological department, a progressive proximally pronounced paraparesis, areflexia, and sensory loss with tingling of all extremities were found, which began 10 days before. The modified Erasmus Giullain-Barré Syndrome outcome score (mEGOS) was 3/9 at admission and 1/12 at day 7 of hospitalization. The electrophysiological assessment proved a segmental demyelinating polyneuropathy and cerebrospinal fluid examination showed an albuminocytologic dissociation. The neurological symptoms improved significantly during treatment with immunoglobulins. Our case draws attention to the occurrence of GBS also in patients with COVID-19 (coronavirus disease 2019), who did not experience respiratory or general symptoms. It emphasizes that SARS-CoV-2 induces immunological processes, regardless from the lack of prodromic symptoms. However, it is likely that there is a connection between the severity of the respiratory syndrome and further neurological consequences.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Síndrome de Guillain-Barré/etiologia , Pandemias , Pneumonia Viral/complicações , Ageusia/etiologia , Eletromiografia , Feminino , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/fisiopatologia , Síndrome de Guillain-Barré/terapia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Pessoa de Meia-Idade , Neurônios Motores/fisiologia , Condução Nervosa , Transtornos do Olfato/etiologia , Avaliação de Sintomas
12.
PLoS One ; 15(5): e0233300, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32428015

RESUMO

OBJECTIVE: Damage to locus ceruleus neurons could play a part in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis because of impairment of the blood-brain barrier and enhanced neuroinflammation. The locus ceruleus has connections throughout the brain and spinal cord, so the characteristic widespread multifocal pathology in these disorders could be due to damage to different subsets of locus ceruleus neurons. Previous studies have shown that only certain locus ceruleus neurons accumulate the neurotoxic metal mercury. To find out if concentrations of other toxic metals or of essential trace elements also vary between individual locus ceruleus neurons, we used synchrotron X-ray fluorescence microscopy on frozen sections of locus ceruleus neurons taken from people with multiple sclerosis, in whom the locus ceruleus is structurally intact. MATERIALS AND METHODS: Paraffin embedded sections containing the locus ceruleus from seven people with multiple sclerosis were stained with autometallography that demonstrates accumulations of mercury, silver and bismuth. These were compared to maps of multiple elements obtained from frozen sections of locus ceruleus neurons from the same people using X-ray fluorescence microscopy. Neurons in the anterior pons from three of these donors were used as internal controls. RESULTS: Autometallography staining was observed in scattered locus ceruleus neurons from three of the seven donors. X-ray fluorescence microscopy showed variations among individual locus ceruleus neurons in levels of mercury, selenium, iron, copper, lead, bromine, and rubidium. Variations between donors of locus ceruleus neuronal average levels of mercury, iron, copper, and bromine were also detected. Anterior pons neurons contained no mercury, had varied levels of iron, and had lower copper levels than locus ceruleus neurons. CONCLUSIONS: Individual human locus ceruleus neurons contain varying levels of toxic metals and essential trace elements. In contrast, most toxic metals are absent or at low levels in nearby anterior pons neurons. The locus ceruleus plays a role in numerous central nervous system functions, including maintaining the blood-brain-barrier and limiting neuroinflammation. Toxic metals, or alterations in essential trace metals within individual locus ceruleus neurons, could be one factor determining the non-random destruction of locus ceruleus neurons in normal aging and neurodegenerative diseases, and subsequently the sites of the widespread multifocal central nervous system pathology in these disorders.


Assuntos
Locus Cerúleo/metabolismo , Metais Pesados/análise , Neurônios/metabolismo , Oligoelementos/análise , Idoso , Autopsia , Feminino , Intoxicação por Metais Pesados , Humanos , Locus Cerúleo/fisiologia , Pessoa de Meia-Idade , Neurônios Motores/metabolismo , Esclerose Múltipla/metabolismo , Espectrometria por Raios X/métodos , Medula Espinal
13.
PLoS One ; 15(4): e0227464, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240172

RESUMO

Expanded CAG nucleotide repeats are the underlying genetic cause of at least 14 incurable diseases, including Huntington's disease (HD). The toxicity associated with many CAG repeat expansions is thought to be due to the translation of the CAG repeat to create a polyQ protein, which forms toxic oligomers and aggregates. However, recent studies show that HD CAG repeats undergo a non-canonical form of translation called Repeat-associated non-AUG dependent (RAN) translation. RAN translation of the CAG sense and CUG anti-sense RNAs produces six distinct repeat peptides: polyalanine (polyAla, from both CAG and CUG repeats), polyserine (polySer), polyleucine (polyLeu), polycysteine (polyCys), and polyglutamine (polyGln). The toxic potential of individual CAG-derived RAN polypeptides is not well understood. We developed pure C. elegans protein models for each CAG RAN polypeptide using codon-varied expression constructs that preserve RAN protein sequence but eliminate repetitive CAG/CUG RNA. While all RAN polypeptides formed aggregates, only polyLeu was consistently toxic across multiple cell types. In GABAergic neurons, which exhibit significant neurodegeneration in HD patients, codon-varied (Leu)38, but not (Gln)38, caused substantial neurodegeneration and motility defects. Our studies provide the first in vivo evaluation of CAG-derived RAN polypeptides in a multicellular model organism and suggest that polyQ-independent mechanisms, such as RAN-translated polyLeu peptides, may have a significant pathological role in CAG repeat expansion disorders.


Assuntos
Doença de Huntington/genética , Neurônios Motores/metabolismo , Agregados Proteicos/genética , Expansão das Repetições de Trinucleotídeos/genética , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/genética , Modelos Animais de Doenças , Humanos , Doença de Huntington/patologia , Neurônios Motores/patologia , Peptídeos/genética , Peptídeos/metabolismo , Biossíntese de Proteínas , RNA Antissenso/genética , Sequências Repetitivas de Aminoácidos/genética
14.
J Electromyogr Kinesiol ; 52: 102419, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32305018

RESUMO

Motor unit (MU) recordings obtained from surface electromyography (sEMG) decomposition are used to investigate the neural control of muscle in response to interventions, but our understanding of the longer-term reliability of MU variables is limited. This study examined the reliability of MU variables in the flexor carpi radialis (FCR) and tibialis anterior (TA) over a three-month period. Forty college-aged participants completed isometric wrist flexion (n = 20) and dorsiflexion (n = 20). There were 3 maximal isometric voluntary contractions (MVC) and 3 ramp contractions to 60% of MVC on four separate sessions separated by a total of 13 weeks. Intraclass correlation coefficients (ICC) were calculated from a fully nested ANOVA model. Maximal force was highly reliable (ICC = 0.94-0.99). The ICC values ranged from 0.49 to 0.92 for the FCR MU variables and from 0.58 to 0.96 for the TA MU variables. All MU variables exhibited a high degree of stability of means across test session and consistency within subjects, with the exception of the number of MUs detected in the TA. Poor ICC values did not reflect poor reliability but rather, convergence towards a narrow range of physiologically normal values. Surface EMG decomposition of a large population of MUs showed no differences in common drive between FCR (0.273) and for the TA (0.267) across test sessions. Forty percent of the sampled MUs in both muscles had a common drive of 0.30 or greater, which provides indirect support for the validity of the decompositions. MU variables may be used to monitor adaptations to a longer-term intervention study.


Assuntos
Eletromiografia/normas , Contração Isométrica , Neurônios Motores/fisiologia , Músculo Esquelético/fisiologia , Adulto , Eletromiografia/métodos , Feminino , Humanos , Masculino , Músculo Esquelético/inervação , Reprodutibilidade dos Testes , Punho/fisiologia
15.
J Electromyogr Kinesiol ; 52: 102420, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32334377

RESUMO

The objective of this study was to establish the effects of transspinal stimulation on short-latency tibialis anterior (TA) flexion reflex during walking in healthy humans. Single pulse transspinal stimulation was delivered at a conditioning-test (C-T) interval either after (~20 ms) or simultaneously with the last pulse of the pulse train (0 ms) delivered to the medial arch of the right foot. Transspinal stimulation was delivered at sub- and supra-threshold intensities of the spinally-mediated TA transspinal evoked potential. Stimulation was delivered randomly at different phases of the step cycle, based on the foot switch threshold signal, which was divided into 16 equal bins. The TA flexion reflex facilitation under control conditions occurred at heel contact and then progressively from late stance phase reaching its peak at early and late swing phases. Transspinal stimulation at a negative and suprathreshold 0 ms C-T interval depressed flexion reflex excitability at all phases of the step cycle. The short-latency TA flexion reflex depression was possibly mediated through spinal inhibitory interneurons acting at both pre- and post- motoneuronal sites or by transspinal stimulation affecting directly the activity of the flexor half spinal center. These results reveal direct actions of transspinal stimulation on human spinal locomotor networks.


Assuntos
Neurônios Motores/fisiologia , Músculo Esquelético/fisiologia , Reflexo , Medula Espinal/fisiologia , Caminhada , Adulto , Estimulação Elétrica , Feminino , Pé/fisiologia , Humanos , Masculino , Músculo Esquelético/inervação , Inibição Neural , Medula Espinal/citologia
16.
PLoS One ; 15(4): e0231600, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294113

RESUMO

Charcot-Marie-Tooth (CMT) disease is an inherited peripheral motor and sensory neuropathy. The disease is divided into demyelinating (CMT1) and axonal (CMT2) neuropathies, and although we have gained molecular information into the details of CMT1 pathology, much less is known about CMT2. Due to its clinical and genetic heterogeneity, coupled with a lack of animal models, common underlying mechanisms remain elusive. In order to gain an understanding of the normal function of genes associated with CMT2, and to draw direct comparisons between them, we have studied the behavioural, cellular and molecular consequences of mutating nine different genes in the nematode Caenorhabditis elegans (lin-41/TRIM2, dyn-1/DNM2, unc-116/KIF5A, fzo-1/MFN2, osm-9/TRPV4, cua-1/ATP7A, hsp-25/HSPB1, hint-1/HINT1, nep-2/MME). We show that C. elegans defective for these genes display debilitated movement in crawling and swimming assays. Severe morphological defects in cholinergic motors neurons are also evident in two of the mutants (dyn-1 and unc-116). Furthermore, we establish methods for quantifying muscle morphology and use these to demonstrate that loss of muscle structure occurs in the majority of mutants studied. Finally, using electrophysiological recordings of neuromuscular junction (NMJ) activity, we uncover reductions in spontaneous postsynaptic current frequency in lin-41, dyn-1, unc-116 and fzo-1 mutants. By comparing the consequences of mutating numerous CMT2-related genes, this study reveals common deficits in muscle structure and function, as well as NMJ signalling when these genes are disrupted.


Assuntos
Comportamento Animal/fisiologia , Proteínas de Caenorhabditis elegans/genética , Doença de Charcot-Marie-Tooth/genética , Atividade Motora/genética , Junção Neuromuscular/patologia , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans , Doença de Charcot-Marie-Tooth/patologia , Doença de Charcot-Marie-Tooth/fisiopatologia , Neurônios Colinérgicos/patologia , Modelos Animais de Doenças , Heterogeneidade Genética , Humanos , Neurônios Motores/patologia , Músculo Esquelético/citologia , Músculo Esquelético/inervação , Músculo Esquelético/fisiopatologia , Mutação , Técnicas de Patch-Clamp , Potenciais Sinápticos/fisiologia
17.
Am J Obstet Gynecol ; 223(2): 256.e1-256.e9, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32283072

RESUMO

BACKGROUND: Despite undisputable benefits, midtrimester prenatal surgery is not a cure for myelomeningocele (MMC): residual intracranial and motor deficits leading to lifelong handicap question the timing of prenatal surgery. Indeed, the timing and intensity of intrauterine spinal cord injury remains ill defined. OBJECTIVE: We aimed to describe the natural history of neuronal loss in MMC in utero based on postmortem pathology. STUDY DESIGN: Pathology findings were analyzed in 186 cases of myelomeningocele with lesion level between S1 and T1. Using a case-control, cross-sectional design, we investigated the timewise progression and topographic extension of neuronal loss between 13 and 39 weeks. Motor neurons were counted on histology at several spinal levels in 54 isolated MMC meeting quality criteria for cell counting. These were expressed as observed-to-expected ratios, after matching for gestational age and spinal level with 41 controls. RESULTS: Chiari II malformation increased from 30.7% to 91.6% after 16 weeks. The exposed spinal cord displayed early, severe, and progressive neuronal loss: the observed-to-expected count dropped from 17% to ≤2% after 16 weeks. Neuronal loss extended beyond the lesion to the upper levels: in cases <16 weeks, the observed-to-expected motor neuron count was 60% in the adjacent spinal cord, decreasing at a rate of 16% per week. Progressive loss was also found in the upper thoracic cord, but in much smaller proportions. The observed-over-expected ratio of motor neurons was not correlated with the level of myelomeningocele. CONCLUSIONS: Significant neuronal loss is present ≤16 weeks in the exposed cord and progressively extends cranially. Earlier prenatal repair (<16 weeks) could prevent Chiari II malformation in 69.3% of cases, rescue the 17% remaining motor neurons in the exposed cord, and prevent the extension to the upper spinal cord.


Assuntos
Malformação de Arnold-Chiari/patologia , Idade Gestacional , Meningomielocele/patologia , Neurônios Motores/patologia , Medula Espinal/patologia , Aborto Induzido , Malformação de Arnold-Chiari/embriologia , Autopsia , Progressão da Doença , Feminino , Terapias Fetais , Humanos , Vértebras Lombares , Meningomielocele/embriologia , Meningomielocele/cirurgia , Procedimentos Neurocirúrgicos , Gravidez , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Estudos Retrospectivos , Sacro , Vértebras Torácicas
18.
Proc Natl Acad Sci U S A ; 117(19): 10565-10574, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32345721

RESUMO

Numerous mutations that impair retrograde membrane trafficking between endosomes and the Golgi apparatus lead to neurodegenerative diseases. For example, mutations in the endosomal retromer complex are implicated in Alzheimer's and Parkinson's diseases, and mutations of the Golgi-associated retrograde protein (GARP) complex cause progressive cerebello-cerebral atrophy type 2 (PCCA2). However, how these mutations cause neurodegeneration is unknown. GARP mutations in yeast, including one causing PCCA2, result in sphingolipid abnormalities and impaired cell growth that are corrected by treatment with myriocin, a sphingolipid synthesis inhibitor, suggesting that alterations in sphingolipid metabolism contribute to cell dysfunction and death. Here we tested this hypothesis in wobbler mice, a murine model with a homozygous partial loss-of-function mutation in Vps54 (GARP protein) that causes motor neuron disease. Cytotoxic sphingoid long-chain bases accumulated in embryonic fibroblasts and spinal cords from wobbler mice. Remarkably, chronic treatment of wobbler mice with myriocin markedly improved their wellness scores, grip strength, neuropathology, and survival. Proteomic analyses of wobbler fibroblasts revealed extensive missorting of lysosomal proteins, including sphingolipid catabolism enzymes, to the Golgi compartment, which may contribute to the sphingolipid abnormalities. Our findings establish that altered sphingolipid metabolism due to GARP mutations contributes to neurodegeneration and suggest that inhibiting sphingolipid synthesis might provide a useful strategy for treating these disorders.


Assuntos
Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Esfingolipídeos/metabolismo , Animais , Modelos Animais de Doenças , Endossomos/metabolismo , Ácidos Graxos Monoinsaturados/farmacologia , Feminino , Fibroblastos/metabolismo , Complexo de Golgi/metabolismo , Masculino , Camundongos , Camundongos Mutantes Neurológicos , Doença dos Neurônios Motores/genética , Doença dos Neurônios Motores/metabolismo , Doença dos Neurônios Motores/patologia , Neurônios Motores/metabolismo , Células-Tronco Embrionárias Murinas , Mutação , Malformações do Sistema Nervoso/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Transporte Proteico , Proteômica , Proteínas de Transporte Vesicular/metabolismo
20.
Chemosphere ; 253: 126762, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32302915

RESUMO

17ß-trenbolone (17ß-TBOH) is one of the dominant metabolites of trenbolone acetate, which is widely applied in beef cattle operations around the globe. The effects of environmental concentrations of 17ß-trenbolone on the early development of zebrafish embryos have received very little attention. Melatonin could regulate sleep-wake cycle and plays a protective role in various adverse conditions. Here, environmentally realistic concentrations of 17ß-trenbolone (1 ng/L, 10 ng/L, 50 ng/L) has been exposure to zebrafish embryos at 2 h postfertilization (hpf). The results showed that 10 ng/L and 50 ng/L 17ß-trenbolone disturbed the distribution of caudal primary motoneurons and downregulated expression of motoneuron development related genes along with locomotion decreasing. While melatonin could recover the detrimental effects caused by 17ß-trenbolone. Interestingly, 17ß-trenbolone exposure increased waking activity and decreased rest even in a low dose (1 ng/L). Moreover, it upregulated hypocretin/orexin (Hcrt) signaling which promotes wakefulness. Melatonin restored the insomnia-like alternation induced by 17ß-trenbolone exposure. Collectively, we conclude that 17ß-trenbolone disturbed motoneuron development and altered sleep/wake behavior, while melatonin could alleviate the deleterious influence on motoneuron development and recover the circadian rhythm.


Assuntos
Comportamento Animal/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Melatonina/farmacologia , Atividade Motora/efeitos dos fármacos , Distúrbios do Início e da Manutenção do Sono/prevenção & controle , Acetato de Trembolona/toxicidade , Peixe-Zebra , Animais , Bovinos , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/genética , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/fisiologia , Desenvolvimento Embrionário/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Orexinas/genética , Fenótipo , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente
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