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2.
Neurotherapeutics ; 16(4): 1149-1166, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31342410

RESUMO

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder in which the neuromuscular junction progressively degenerates, leading to movement difficulties, paralysis, and eventually death. ALS is currently being treated by only two FDA-approved drugs with modest efficacy in slowing disease progression. Often, the translation of preclinical findings to bedside terminates prematurely as the evaluation of potential therapeutic compounds focuses on a single study or a single animal model. To circumscribe these issues, we screened 3,765 novel small molecule derivatives of pimozide, a recently identified repurposed neuroleptic for ALS, in Caenorhabditis elegans, confirmed the hits in zebrafish and validated the most active compounds in mouse genetic models. Out of the 27 small molecules identified from the high-throughput screen in worms, 4 were found to recover locomotor defects in C. elegans and genetic zebrafish models of ALS. TRVA242 was identified as the most potent compound as it significantly improved efficiency in rescuing locomotor, motorneuron, and neuromuscular junction synaptic deficits in a C. elegans TDP-43 model and in multiple zebrafish genetic (TDP-43, SOD1, and C9ORF72) models of ALS. The actions of TRVA242 were also conserved in a mammalian model as it also stabilized neuromuscular junction deficits in a mouse SOD1 model of ALS. Compounds such as TRVA242 therefore represent new potential therapeutics for the treatment of ALS.


Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Proteína C9orf72/genética , Modelos Animais de Doenças , Junção Neuromuscular/genética , Superóxido Dismutase-1/genética , Esclerose Lateral Amiotrófica/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans , Proteínas de Ligação a DNA/administração & dosagem , Proteínas de Ligação a DNA/metabolismo , Humanos , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/metabolismo , Técnicas de Cultura de Órgãos , Pimozida/administração & dosagem , Pimozida/metabolismo , Peixe-Zebra
3.
JCI Insight ; 2(22)2017 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-29202456

RESUMO

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal disorder with no effective treatment. We used simple genetic models of ALS to screen phenotypically for potential therapeutic compounds. We screened libraries of compounds in C. elegans, validated hits in zebrafish, and tested the most potent molecule in mice and in a small clinical trial. We identified a class of neuroleptics that restored motility in C. elegans and in zebrafish, and the most potent was pimozide, which blocked T-type Ca2+ channels in these simple models and stabilized neuromuscular transmission in zebrafish and enhanced it in mice. Finally, a short randomized controlled trial of sporadic ALS subjects demonstrated stabilization of motility and evidence of target engagement at the neuromuscular junction. Simple genetic models are, thus, useful in identifying promising compounds for the treatment of ALS, such as neuroleptics, which may stabilize neuromuscular transmission and prolong survival in this disease.


Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Antipsicóticos/farmacocinética , Antipsicóticos/uso terapêutico , Doenças da Junção Neuromuscular/tratamento farmacológico , Animais , Caenorhabditis elegans , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio Tipo T/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Tolerância a Medicamentos , Feminino , Camundongos , Junção Neuromuscular/efeitos dos fármacos , Pimozida/farmacologia , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismo
4.
J Neurosci ; 37(37): 8901-8918, 2017 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-28821658

RESUMO

Denervation of the neuromuscular junction (NMJ) precedes the loss of motor neurons (MNs) in amyotrophic lateral sclerosis (ALS). ALS is characterized by a motor unit (MU)-dependent vulnerability where MNs with fast-fatigable (FF) characteristics are lost first, followed by fast fatigue-resistant (FR) and slow (S) MNs. However, changes in NMJ properties as a function of MU types remain debated. We hypothesized that NMJ synaptic functions would be altered precociously in an MU-specific manner, before structural alterations of the NMJ. Synaptic transmission and morphological changes of NMJs have been explored in two nerve-muscle preparations of male SOD1G37R mice and their wild-type (WT) littermates: the soleus (S and FR MU); and the extensor digitorum longus (FF MU). S, FR, and FF NMJs of WT mice showed distinct synaptic properties from which we build an MU synaptic profile (MUSP) that reports MU-dependent NMJ synaptic properties. At postnatal day 180 (P180), FF and S NMJs of SOD1 already showed, respectively, lower and higher quantal content compared with WT mice, before signs of MN death and before NMJ morphological alterations. Changes persisted in both muscles until preonset (P380), while denervation was frequent in the mutant mouse. MN death was evident at this stage. Additional changes occurred at clinical disease onset (P450) for S and FR MU. As a whole, our results reveal a reversed MUSP in SOD1 mutants and highlight MU-specific synaptic changes occurring in a precise temporal sequence. Importantly, changes in synaptic properties appear to be good predictors of vulnerability to neurodegeneration.SIGNIFICANCE STATEMENT The inadequate excitability of motor neurons and their output, the neuromuscular junctions (NMJs), has been considered a key factor in the detrimental outcome of the motor function in amyotrophic lateral sclerosis. However, a conundrum persists at the NMJ whereby persistent but incoherent opposite neurotransmission changes have been reported to take place. This article untangles this conundrum by systematically analyzing the changes in synaptic properties over the course of the disease progression as a function of the motor unit type. This temporal analysis reveals that early synaptic alterations evolve with disease progression but precede NMJ neurodegeneration. These data provide a novel framework of analysis and comparison of synaptic transmission alterations in neurodegenerative disorders.


Assuntos
Esclerose Lateral Amiotrófica/fisiopatologia , Neurônios Motores/patologia , Fibras Musculares Esqueléticas/patologia , Junção Neuromuscular/patologia , Plasticidade Neuronal , Sinapses/patologia , Transmissão Sináptica , Esclerose Lateral Amiotrófica/patologia , Animais , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Superóxido Dismutase-1/genética
5.
J Neurosci ; 35(2): 688-706, 2015 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-25589763

RESUMO

Amyotrophic lateral sclerosis (ALS) is a late-onset neuromuscular disease characterized by progressive loss of motor neurons (MNs) preceded by neuromuscular junction (NMJ) denervation. Despite the importance of NMJ denervation in ALS, the mechanisms involved remain unexplored and ill defined. The contribution of glial cells in the disease has been highlighted, including axonal Schwann cell activation that precedes the decline of motor function and the onset of hindlimb paralysis. Because NMJ denervation occurs early in the process and that perisynaptic Schwann cells (PSCs), glial cells at the NMJ, regulate morphological stability, integrity, and repair of the NMJ, one could predict that PSC functions would be altered even before denervation, contributing to NMJ malfunctions. We tested this possibility using a slowly progressive model of ALS (SOD1(G37R) mice). We observed a normal NMJ organization at a presymptomatic stage of ALS (120 d), but PSC detection of endogenous synaptic activity revealed by intracellular Ca(2+) changes was enhanced compared with their wild-type littermates. This inappropriate PSC decoding ability was associated with an increased level of neurotransmitter release and dependent on intrinsic glial properties related to enhanced muscarinic receptor activation. The alteration of PSC muscarinic receptor functions also persists during the preonset stage of the disease and became dependent on MN vulnerability with age. Together, these results suggest that PSC properties are altered in the disease process in a manner that would be detrimental for NMJ repair. The impairments of PSC functions may contribute to NMJ dysfunction and ALS pathogenesis.


Assuntos
Esclerose Lateral Amiotrófica/fisiopatologia , Junção Neuromuscular/fisiopatologia , Células de Schwann/fisiologia , Esclerose Lateral Amiotrófica/genética , Animais , Cálcio/metabolismo , Camundongos , Junção Neuromuscular/metabolismo , Receptores Muscarínicos/metabolismo , Células de Schwann/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase-1 , Potenciais Sinápticos
6.
Front Neuroeng ; 5: 5, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22493577

RESUMO

Previous studies have shown that neural activity in primate dorsal premotor cortex (PMd) can simultaneously represent multiple potential movement plans, and that activity related to these movement options is modulated by their relative subjective desirability. These findings support the hypothesis that decisions about actions are made through a competition within the same circuits that guide the actions themselves. This hypothesis further predicts that the very same cells that guide initial decisions will continue to update their activities if an animal changes its mind. For example, if a previously selected movement option suddenly becomes unavailable, the correction will be performed by the same cells that selected the initial movement, as opposed to some different group of cells responsible for online guidance. We tested this prediction by recording neural activity in the PMd of a monkey performing an instructed-delay reach selection task. In the task, two targets were simultaneously presented and their border styles indicated whether each would be worth 1, 2, or 3 juice drops. In a random subset of trials (FREE), the monkey was allowed a choice while in the remaining trials (FORCED) one of the targets disappeared at the time of the GO signal. In FORCED-LOW trials the monkey was forced to move to the less valuable target and started moving either toward the new target (Direct) or toward the target that vanished and then curved to reach the remaining one (Curved). Prior to the GO signal, PMd activity clearly reflected the monkey's subjective preference, predicting his choices in FREE trials even with equally valued options. In FORCED-LOW trials, PMd activity reflected the switch of the monkey's plan as early as 100 ms after the GO signal, well before movement onset (MO). This confirms that the activity is not related to feedback from the movement itself, and suggests that PMd continues to participate in action selection even when the animal changes its mind on-line. These findings were reproduced by a computational model suggesting that switches between action plans can be explained by the same competition process responsible for initial decisions.

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