RESUMO
Axonal degeneration is observed in early stages of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). This degeneration generally precedes apoptosis and therefore may be a promising therapeutic target. An increasing number of genes have been identified to actively regulate axonal degeneration and regeneration; however, only a few potential therapeutic targets have been identified in the context of neurodegenerative diseases. Here we investigate DLK-1, a major axonal regeneration pathway and its contribution to axonal degeneration phenotypes in several Caenorhabditis elegans ALS models. From this pathway, we identified the poly (ADP-ribose) (PAR) polymerases (PARP) PARP-1 and PARP-2 as the most consistent modifiers of axonal degeneration in our models of ALS. Genetic and pharmacological inhibition of PARP-1 and PARP-2 reduces axonal degeneration and improves related motor phenotypes.
Assuntos
Esclerose Lateral Amiotrófica , Proteínas de Caenorhabditis elegans , Doenças Neurodegenerativas , Difosfato de Adenosina , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , MAP Quinase Quinase Quinases , Doenças Neurodegenerativas/metabolismo , Poli Adenosina Difosfato Ribose/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , RiboseRESUMO
When speed changes during locomotion, both temporal and spatial parameters of the pattern must adjust. Moreover, at slow speeds the step-to-step pattern becomes increasingly variable. The objectives of the present study were to assess if the spinal locomotor network adjusts both temporal and spatial parameters from slow to moderate stepping speeds and to determine if it contributes to step-to-step variability in left-right symmetry observed at slow speeds. To determine the role of the spinal locomotor network, the spinal cord of 6 adult cats was transected (spinalized) at low thoracic levels and the cats were trained to recover hindlimb locomotion. Cats were implanted with electrodes to chronically record electromyography (EMG) in several hindlimb muscles. Experiments began once a stable hindlimb locomotor pattern emerged. During experiments, EMG and bilateral video recordings were made during treadmill locomotion from 0.1 to 0.4 m/s in 0.05 m/s increments. Cycle and stance durations significantly decreased with increasing speed, whereas swing duration remained unaffected. Extensor burst duration significantly decreased with increasing speed, whereas sartorius burst duration remained unchanged. Stride length, step length, and the relative distance of the paw at stance offset significantly increased with increasing speed, whereas the relative distance at stance onset and both the temporal and spatial phasing between hindlimbs were unaffected. Both temporal and spatial step-to-step left-right asymmetry decreased with increasing speed. Therefore, the spinal cord is capable of adjusting both temporal and spatial parameters during treadmill locomotion, and it is responsible, at least in part, for the step-to-step variability in left-right symmetry observed at slow speeds.
Assuntos
Membro Posterior/fisiologia , Locomoção/fisiologia , Medula Espinal/fisiologia , Animais , Fenômenos Biomecânicos , Gatos , Eletrodos Implantados , Eletromiografia , Feminino , Lateralidade Funcional , Membro Posterior/fisiopatologia , Masculino , Vias Neurais/fisiologia , Vias Neurais/fisiopatologia , Recuperação de Função Fisiológica/fisiologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Vértebras Torácicas , Gravação em VídeoRESUMO
Background: Recent advances linking gut dysbiosis with neurocognitive disorders such as Alzheimer's disease (AD) suggest that the microbiota-gut-brain axis could be targeted for AD prevention, management, or treatment. Objective: We sought to identify probiotics that can delay Aß-induced paralysis. Methods: Using C. elegans expressing human amyloid-ß (Aß)1-42 in body wall muscles (GMC101), we assessed the effects of several probiotic strains on paralysis. Results: We found that Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179, but not their supernatants or heat-treated forms, delayed paralysis and prolonged lifespan without affecting the levels of amyloid-ß aggregates. To uncover the mechanism involved, we explored the role of two known pathways involved in neurogenerative diseases, namely mitophagy, via deletion of the mitophagy factor PINK-1, and fatty acid desaturation, via deletion of the Δ9 desaturase FAT-5. Pink-1 deletion in GMC101 worms did not modify the life-prolonging and anti-paralysis effects of HA-114 but reduced the protective effect of R0179 against paralysis without affecting its life-prolonging effect. Upon fat5 deletion in GMC101 worms, the monounsaturated C14:1 and C16:1 FAs conserved their beneficial effect while the saturated C14:0 and C16:0 FAs did not. The beneficial effects of R0179 on both lifespan and paralysis remained unaffected by fat-5 deletion, while the beneficial effect of HA-114 on paralysis and lifespan was significantly reduced. Conclusions: Collectively with clinical and preclinical evidence in other models, our results suggest that HA-114 or R0179 could be studied as potential therapeutical adjuncts in neurodegenerative diseases such as AD.
RESUMO
The human microbiota is believed to influence health. Microbiome dysbiosis may be linked to neurological conditions like Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. We report the ability of a probiotic bacterial strain in halting neurodegeneration phenotypes. We show that Lacticaseibacillus rhamnosus HA-114 is neuroprotective in C. elegans models of amyotrophic lateral sclerosis and Huntington's disease. Our results show that neuroprotection from L. rhamnosus HA-114 is unique from other L. rhamnosus strains and resides in its fatty acid content. Neuroprotection by L. rhamnosus HA-114 requires acdh-1/ACADSB, kat-1/ACAT1 and elo-6/ELOVL3/6, which are associated with fatty acid metabolism and mitochondrial ß-oxidation. Our data suggest that disrupted lipid metabolism contributes to neurodegeneration and that dietary intervention with L. rhamnosus HA-114 restores lipid homeostasis and energy balance through mitochondrial ß-oxidation. Our findings encourage the exploration of L. rhamnosus HA-114 derived interventions to modify the progression of neurodegenerative diseases.
Assuntos
Esclerose Lateral Amiotrófica , Doença de Huntington , Lacticaseibacillus rhamnosus , Humanos , Animais , Lacticaseibacillus , Ácidos Graxos , Caenorhabditis elegansRESUMO
Mutations in the human DNA/RNA binding protein FUS are associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration, including some aggressive and juvenile onset forms. Cytoplasmic inclusions of human FUS proteins are observed in various neurodegenerative disorders, such as Huntington's disease or spinocerebellar ataxia, suggesting that FUS proteinopathy may be a key player in neurodegeneration. To better understand the pathogenic mechanisms of FUS, we created single copy transgenic Caenorhabditis elegans strains expressing full-length, untagged human FUS in the worm's GABAergic neurons. These transgenic worms expressing human mutant FUS (mFUS) display the same ALS-associated phenotypes than our previous multiple copy transgenic model, including adult-onset age-dependent loss of motility, progressive paralysis and GABAergic neurodegeneration. These phenotypes are distinct from the transgenic worms expressing human wild-type FUS (wtFUS). We introduce here our C. elegans single copy transgenic for human mutant FUS motor neuron toxicity that may be used for rapid genetic and pharmacological suppressor screening.
RESUMO
Spinal muscular atrophy (SMA) is a devastating autosomal recessive neuromuscular disease resulting in muscle atrophy and neurodegeneration, and is the leading genetic cause of infant death. SMA arises when there are homozygous deletion mutations in the human SMN1 gene, leading to a decrease in corresponding SMN1 protein. Although SMN1 is expressed across multiple tissue types, much of the previous research into SMA focused on the neuronal aspect of the disease, overlooking many of the potential non-neuronal aspects of the disease. Therefore, we sought to address this gap in knowledge by modeling SMA in the nematode Caenorhabditis elegans We mutated a previously uncharacterized allele, which resulted in the onset of mild SMA-like phenotypes, allowing us to monitor the onset of phenotypes at different stages. We observed that these mutant animals recapitulated many key features of the human disease, and most importantly, we observed that muscle dysfunction preceded neurodegeneration. Furthermore, we tested the therapeutic efficacy of targeting endoplasmic reticulum (ER) stress in non-neuronal cells and found it to be more effective than targeting ER stress in neuronal cells. We also found that the most potent therapeutic potential came from a combination of ER- and neuromuscular junction-targeted drugs. Together, our results suggest an important non-neuronal component of SMA pathology and highlight new considerations for therapeutic intervention.