Neuromuscular organoids model spinal neuromuscular pathologies in C9orf72 amyotrophic lateral sclerosis

Cell Reports, Journal Year: 2024, Volume and Issue: 43(3), P. 113892 - 113892

Published: March 1, 2024

Hexanucleotide repeat expansions in the C9orf72 gene are most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Due to lack trunk neuromuscular organoids (NMOs) from ALS patients' induced pluripotent stem cells (iPSCs), an organoid system was missing model spinal neurodegeneration. With patient-derived iPSCs isogenic controls, we used NMO containing cord neural peripheral muscular tissues show that NMOs could defects ALS, including contraction weakness, denervation, loss Schwann cells. The neurons astrocytes manifested RNA foci dipeptide proteins. Acute treatment with unfolded protein response inhibitor GSK2606414 increased glutamatergic 2-fold reduced aggregation autophagy. This study provides for pathologies its application drug testing.

Language: Английский

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Amyotrophic Lateral Sclerosis Pathoetiology and Pathophysiology: Roles of Astrocytes, Gut Microbiome, and Muscle Interactions via the Mitochondrial Melatonergic Pathway, with Disruption by Glyphosate-Based Herbicides

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 24(1), P. 587 - 587

Published: Dec. 29, 2022

The pathoetiology and pathophysiology of motor neuron loss in amyotrophic lateral sclerosis (ALS) are still to be determined, with only a small percentage ALS patients having known genetic risk factor. article looks integrate wider bodies data on the biological underpinnings ALS, highlighting integrative role alterations mitochondrial melatonergic pathways systemic factors regulating this pathway across number crucial hubs pathophysiology, namely glia, gut, muscle/neuromuscular junction. It is proposed that suppression underpins changes muscle brain-derived neurotrophic factor, its mimic, N-acetylserotonin, leading lack metabolic trophic support at neuromuscular attenuation astrocytes prevents activation toll-like receptor agonists-induced pro-inflammatory transcription factors, NF-kB, yin yang 1, from built-in limitation inflammatory induction arises their synchronized melatonin release. Such maintained astrocyte activation, coupled heightened microglia reactivity, an important driver susceptibility ALS. Two gut dysbiosis/permeability pineal mediate many beneficial effects via capacity upregulate central cells. may seen as core aspect cellular function, increasing reactive oxygen species (ROS), ROS-induced microRNAs, thereby altering patterning genes induced. increased occupational farmers, gardeners, sportsmen women intimately linked exposure, whilst being physically active, widely used glyphosate-based herbicides. This has numerous research treatment implications.

Language: Английский

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Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice

JCI Insight, Journal Year: 2023, Volume and Issue: 8(9)

Published: March 16, 2023

Gain-of-function mutations in the housekeeping gene GARS1, which lead to expression of toxic versions glycyl-tRNA synthetase (GlyRS), cause selective motor and sensory pathology characterizing Charcot-Marie-Tooth disease (CMT). Aberrant interactions between GlyRS mutants different proteins, including neurotrophin receptor tropomyosin kinase B (TrkB), underlie CMT type 2D (CMT2D); however, our pathomechanistic understanding this untreatable peripheral neuropathy remains incomplete. Through intravital imaging sciatic nerve, we show that CMT2D mice displayed early persistent disturbances axonal transport neurotrophin-containing signaling endosomes vivo. We discovered brain-derived neurotrophic factor (BDNF)/TrkB impairments correlated with disruption overall neuropathology inhibition pathway at nerve-muscle interface perturbed endosome wild-type axons. Accordingly, supplementation muscles BDNF, but not other neurotrophins, completely restored physiological neuropathic mice. Together, these findings suggest selectively targeting BDNF-boosting therapies could represent a viable therapeutic strategy for CMT2D.

Language: Английский

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Common mechanisms underlying axonal transport deficits in neurodegenerative diseases: a mini review

Frontiers in Molecular Neuroscience, Journal Year: 2023, Volume and Issue: 16

Published: April 24, 2023

Many neurodegenerative diseases including Alzheimer’s disease, Parkinson’s and amyotrophic lateral sclerosis are characterized by the accumulation of pathogenic proteins abnormal localization organelles. These pathological features may be related to axonal transport deficits in neurons, which lead failures protein targeting specific sites for degradation organelle transportation designated areas needed normal physiological functioning. Axonal most likely early events such gradually loss integrity other degenerative changes. In this review, we investigated reports mechanisms underlying development a variety common diseases, as sclerosis, disease Huntington’s provide new ideas therapeutic targets that used process. The can summarized follows: (1) motor changes expression levels post-translational modification alteration; (2) microtubules reducing stability disrupting tracks; (3) cargoes diminished binding proteins. Future studies should determine defects disease-specific whether they suitable diseases.

Language: Английский

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Targeting brain‐derived neurotrophic factor in the treatment of neurodegenerative diseases: A review

Neuroprotection/Neuroprotection (Chichester, England. Print), Journal Year: 2024, Volume and Issue: 2(2), P. 67 - 78

Published: May 2, 2024

Abstract Neurodegenerative diseases, marked by the gradual death of neurons, present a significant and growing public health challenge. Brain‐derived neurotrophic factor (BDNF) is crucial for survival, development, synaptic plasticity neurons. Studies have consistently demonstrated that perturbed BDNF communication pathways are associated with development progression neurodegenerative conditions, underscoring their potential as therapeutic targets. This review aimed to summarize existing findings regarding expression, metabolism, signaling transduction. Furthermore, we reviewed intricate roles in elucidating contributions disease onset progression. The latest advancements targeting treatment including small molecules, nucleic acid‐based therapeutics, antibody‐based approaches, were also summarized. Despite recent strides, challenges persist, lack comprehensive understanding modulation across diverse contexts absence clinically approved BDNF‐targeted drugs.

Language: Английский

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Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 195, P. 106501 - 106501

Published: April 6, 2024

Charcot-Marie-Tooth disease (CMT) is a genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which transfer amino acids to partner tRNAs for protein synthesis, represent the largest family genetically linked CMT aetiology, suggesting pathomechanistic commonalities. Dominant intermediate type C (DI-CMTC) YARS1 driving toxic gain-of-function encoded tyrosyl-tRNA (TyrRS), mediated exposure of consensus neomorphic surfaces through conformational changes mutant protein. In this study, we first showed that human DI-CMTC-causing TyrRSE196K mis-interacts with extracellular domain BDNF receptor TrkB, an aberrant association have previously characterised several glycyl-tRNA synthetases 2D (CMT2D). We then performed temporal neuromuscular assessments YarsE196K mice modelling DI-CMT. determined homozygotes display selective, age-dependent impairment vivo axonal transport neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. This replicated injection recombinant TyrRSE196K, but not TyrRSWT, into muscles wild-type Augmenting DI-CMTC muscles, or muscle-specific gene therapy, resulted complete correction. Therefore, work identifies non-cell autonomous pathomechanism common ARS-related neuropathies, and highlights potential boosting levels as therapeutic strategy.

Language: Английский

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AAV-NRIP gene therapy ameliorates motor neuron degeneration and muscle atrophy in ALS model mice

Skeletal Muscle, Journal Year: 2024, Volume and Issue: 14(1)

Published: July 24, 2024

Abstract Background Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration, leading to neuromuscular junction (NMJ) dismantling and severe muscle atrophy. The nuclear receptor interaction protein (NRIP) functions as a multifunctional protein. It directly interacts with calmodulin or α-actinin 2, serving calcium sensor for contraction maintaining sarcomere integrity. Additionally, NRIP binds the acetylcholine (AChR) NMJ stabilization. Loss of in muscles results degeneration abnormal architecture, resembling ALS phenotypes. Therefore, we hypothesize that could be therapeutic factor ALS. Methods We used SOD1 G93A mice, expressing human ALS-linked mutation, an model. An adeno-associated virus vector encoding gene (AAV-NRIP) was generated injected into mice at 60 days age, before disease onset. Pathological behavioral changes were measured evaluate effects AAV-NRIP on progression mice. Results exhibited lower expression than wild-type both spinal cord skeletal tissues. Forced through intramuscular injection observed retrogradely transduced cord. therapy enhanced movement distance rearing frequencies Moreover, increased myofiber size slow myosin expression, ameliorated axon terminal denervation NMJ, number α-motor neurons (α-MNs) compound action potential (CMAP) Conclusions ameliorates atrophy, transmission improved Collectively, drug

Language: Английский

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Modulating Effects of Zingiberaceae Phenolic Compounds on Neurotrophic Factors and Their Potential as Neuroprotectants in Brain Disorders and Age-Associated Neurodegenerative Disorders: A Review

Nutrients, Journal Year: 2023, Volume and Issue: 15(11), P. 2564 - 2564

Published: May 30, 2023

The Zingiberaceae family possess various phenolic compounds that have significant systemic bioactivities in the brain, including age-related neurodegenerative diseases. Neurotrophins are growth factors protect neurons from oxidative stress, and dysregulation of neurotrophic system may result neurocognitive disease. Phenolic been used traditional complementary medicine (TCM) to improve cognitive functions. These affect expression agents, but their underlying molecular mechanisms require further investigation. Therefore, goal this review is determine functional roles brain disorders disorders. While previous studies proposed for neuroprotective activity these compounds, precise mechanism action remains complex poorly understood. Despite some promising findings, there still shortcomings therapeutic use herbs, current interventions involving appear be clinically insufficient. This article aims summarize recent discoveries several members as neuroprotectants provide first evidence-linked bioactive ingredients prominent family.

Language: Английский

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The Secretome of Human Dental Pulp Stem Cells and Its Components GDF15 and HB-EGF Protect Amyotrophic Lateral Sclerosis Motoneurons against Death

Biomedicines, Journal Year: 2023, Volume and Issue: 11(8), P. 2152 - 2152

Published: July 30, 2023

Amyotrophic lateral sclerosis (ALS) is a fatal and incurable paralytic disorder caused by the progressive death of upper lower motoneurons. Although numerous strategies have been developed to slow disease progression improve life quality, date only few therapeutic treatments are available with still unsatisfactory benefits. The secretome dental pulp stem cells (DPSCs) contains neurotrophic factors that could promote motoneuron survival. Accordingly, DPSCs confer neuroprotective benefits

Language: Английский

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Current potential pathogenic mechanisms of copper-zinc superoxide dismutase 1 (SOD1) in amyotrophic lateral sclerosis

Reviews in the Neurosciences, Journal Year: 2024, Volume and Issue: 35(5), P. 549 - 563

Published: Feb. 21, 2024

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease which damages upper and lower motor neurons (UMN LMN) innervating the muscles of trunk, extremities, head, neck face in cerebrum, brain stem spinal cord, results progressive weakness, atrophy fasciculation muscle innervated by related UMN LMN, accompanying with pathological signs leaded cortical tract lesion. The pathogenesis about ALS not fully understood, no specific drugs are available to cure prevent progression this at present. In review, we reviewed structure associated functions copper-zinc superoxide dismutase 1 (SOD1), discuss why SOD1 crucial ALS, outline pathogenic mechanisms that have been identified recent years, including glutamate-related excitotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, oxidative axonal transport disruption, prion-like propagation, non-cytologic toxicity glial cells. This review will help us deeply understand current field ALS.

Language: Английский

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