Homozygous ALS-linked mutations in TARDBP/TDP-43 lead to hypoactivity and synaptic abnormalities in human iPSC-derived motor neurons

iScience, Journal Year: 2024, Volume and Issue: 27(3), P. 109166 - 109166

Published: Feb. 9, 2024

Cytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43 is a pathological hallmark motor neuron (MN) disease amyotrophic lateral sclerosis (ALS). Furthermore, while mutations in

Language: Английский

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Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOs

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 24, 2024

TDP-43 loss of function induces multiple splicing changes, including a cryptic exon in the amyotrophic lateral sclerosis and fronto-temporal lobar degeneration risk gene UNC13A, leading to nonsense-mediated decay UNC13A transcripts protein. is an active zone protein with integral role coordinating pre-synaptic function. Here, we show depletion severe reduction synaptic transmission, asynchronous pattern network activity. We demonstrate that these deficits are largely driven by single UNC13A. Antisense oligonucleotides targeting robustly rescue levels restore normal function, providing potential new therapeutic approach for ALS other TDP-43-related disorders.

Language: Английский

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Single-domain magnetic particles with motion behavior under electromagnetic AC and DC fields are a fatal cargo in Metropolitan Mexico City pediatric and young adult early Alzheimer, Parkinson, frontotemporal lobar degeneration and amyotrophic lateral sclerosis and in ALS patients

Frontiers in Human Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: Aug. 23, 2024

Metropolitan Mexico City (MMC) children and young adults exhibit overlapping Alzheimer Parkinsons’ diseases (AD, PD) TAR DNA-binding protein 43 pathology with magnetic ultrafine particulate matter (UFPM) industrial nanoparticles (NPs). We studied magnetophoresis, electron microscopy energy-dispersive X-ray spectrometry in 203 brain samples from 14 children, 27 adults, ALS cases/controls. Saturation isothermal remanent magnetization (SIRM), capturing magnetically unstable FeNPs ̴ 20nm, was higher caudate, thalamus, hippocampus, putamen, motor regions subcortical vs. cortical SIRM MMC ≤ 40y. Motion behavior associated exposures 25–100 mT exhibited IRM saturated curves at 50–300 to change NPs position and/or orientation situ . Targeted profiles moving under AC/AD fields could distinguish controls. Motor neuron accumulation potentially interferes action potentials, ion channels, nuclear pores enhances the membrane insertion process when coated lipopolysaccharides. TEM EDX showed 7–20 nm NP Fe, Ti, Co, Ni, V, Hg, W, Al, Zn, Ag, Si, S, Br, Ce, La, Pr abnormal neural vascular organelles. Brain of particles start childhood cytotoxic, hyperthermia, free radical formation, motion 30–50 μT (DC fields) are critical given ubiquitous electric induce damage. Magnetic UFPM/NPs a fatal cargo children’s brains, preventable AD, PD, FTLD, environmental threat. Billions people risk. clearly poisoning ourselves.

Language: Английский

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Amyotrophic lateral sclerosis represents corticomotoneuronal system failure

Muscle & Nerve, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 7, 2024

Several decades have passed since the anterograde corticomotoneuronal hypothesis for amyotrophic lateral sclerosis (ALS) was proposed. The intervening years witnessed its emergent support based on anatomical, pathological, physiological, neuroimaging, and molecular biological studies. evolution of an extensive system appears restricted to human species, with ALS representing a uniquely disease. While some, very select non-human primates limited projections, these tend be absent in all other animals. From general perspective, early clinical features may considered reflect failure system. characteristic loss skilled motor dexterity involving limbs, speech impairment through progressive bulbar dysfunction specifically involve those units having strongest projections. A similar explanation likely underlies unique "split phenotypes" that now been well characterized ALS. Large Betz cells pyramidal projecting neurons, their dendritic arborization, are particularly vulnerable elements exposome such as aging, environmental stress lifestyle changes. Progressive proteosome impairs nucleocytoplasmic shuffling induces toxic but soluble TDP-43 aggregate corticomotoneurons. cell is further accentuated profuse arborizations. Clarification specific genomes neural networks will promote initiation precision medicine approaches directed key structure neurological manifestations ALS,

Language: Английский

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Satellite microglia: marker of traumatic brain injury and regulator of neuronal excitability

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Jan. 16, 2025

Traumatic brain injury is a leading cause of chronic neurologic disability and risk factor for development neurodegenerative disease. However, little known regarding the pathophysiology human traumatic injury, especially in window after acute later life progressive Given proposed mechanisms toxic protein production neuroinflammation as possible initiators or contributors to pathology, we examined phosphorylated tau accumulation, microgliosis astrogliosis using immunostaining orbitofrontal cortex, region often vulnerable across exposures, an age sex-matched cohort community including both mild severe cases midlife. We found that microglial response most prominent interactions with neurons form satellite microglia are increased, even injury. Taking our investigation into mouse model, identified these suppress neuronal excitability control conditions but lose this ability At same time, network hyperexcitability present cortex. Our findings support role loss homeostatic by maladaptive circuit changes occur

Language: Английский

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The dynamic axon initial segment: From neuronal polarity to network homeostasis

Neuron, Journal Year: 2025, Volume and Issue: 113(5), P. 649 - 669

Published: Feb. 12, 2025

The axon initial segment (AIS) is a highly specialized compartment in neurons that resides between axonal and somatodendritic domains. localization of the AIS proximal part essential for its two major functions: generating modulating action potentials maintaining neuron polarity. Recent findings revealed incredibly stable generated from dynamic components can undergo extensive structural functional changes response to alterations activity levels. These activity-dependent structure function have profound consequences neuronal functioning, plasticity has emerged as key regulator network homeostasis. This review highlights functions AIS, architecture, how organization remodeling are influenced by developmental both acute chronic adaptations. It also discusses mechanisms underlying these processes explores dysregulated may contribute brain disorders.

Language: Английский

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TDP-43 pathology is sufficient to drive axon initial segment plasticity and hyperexcitability of spinal motoneurones in vivo in the TDP43-ΔNLS model of Amyotrophic Lateral Sclerosis

Acta Neuropathologica Communications, Journal Year: 2025, Volume and Issue: 13(1)

Published: Feb. 24, 2025

A hyperexcitability of the motor system is consistently observed in Amyotrophic Lateral Sclerosis (ALS) and has been implicated disease pathogenesis. What drives this vast majority patients unknown. This important to know as existing treatments simply reduce all neuronal excitability fail distinguish between pathological changes homeostatic changes. Understanding what initial could therefore provide better treatments. One challenge that represent a heterogeneous population cases are sporadic. feature almost (~97%) (familial sporadic) have common cytoplasmic aggregates protein TDP-43 which normally located nucleus. In our experiments we investigated whether pathology was sufficient increase mechanisms by occurs. We used TDP-43(ΔNLS) mouse model successfully recapitulates controllable way. vivo intracellular recordings demonstrate drive severe hyper-excitability spinal motoneurones. Reductions soma size lengthening constriction axon segments were observed, would contribute enhanced excitability. Resuppression transgene resulted return normal parameters 6–8 weeks. conclude itself but reversible

Language: Английский

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Neural Excitatory/Inhibitory Imbalance in Motor Aging: From Genetic Mechanisms to Therapeutic Challenges

Biology, Journal Year: 2025, Volume and Issue: 14(3), P. 272 - 272

Published: March 7, 2025

Neural excitatory/inhibitory (E/I) imbalance plays a pivotal role in the aging process. However, despite its significant impact, of E/I motor dysfunction and neurodegenerative diseases has not received sufficient attention. This review explores mechanisms underlying through lens balance, emphasizing genetic molecular factors that contribute to this (such as SCN2A, CACNA1C, GABRB3, GRIN2A, SYT, BDNF…). Key regulatory genes, including REST, vps-34, STXBP1, are examined for their roles modulating synaptic activity neuronal function during aging. With insights drawn from ALS, we discuss how disruptions balance pathophysiology age-related dysfunction. The genes discussed above exhibit certain association with neuron (like ALS), relationship had been previously recognized. Innovative therapies, such gene editing technology optogenetic manipulation, emerging promising tools restoring offering hope ameliorating deficits potential these technologies intervene aging-related diseases, challenges direct application human conditions.

Language: Английский

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Trimetazidine, a promising drug for amyotrophic lateral sclerosis, modulates Ca2+ influx in spinal neurons

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

The metabolic modulator trimetazidine (TMZ) is an antianginal recently found to improve skeletal muscle performance in mice models of sarcopenia and Amyotrophic Lateral Sclerosis (ALS). mechanism underlying the effect TMZ on locomotor activity has been proposed rely its ability enhance efficiency with a consequent improvement myogenesis neuromuscular junction (NMJ) function. However, although promising therefore under clinical trials, action not clearly disclosed; here we hypothesized that it might involve modulation neuronal Ca²⁺ flows. We studied dynamics in vivo, by using transgenic zebrafish line Tg(neurod1:GCaMP6f) which expression indicator GCaMP allows visualize neurons larvae. By this elegant tool, demonstrated, for first time, promotes influx spinal likely enhancing motor neuron firing, correlates enhanced drug. Even though elevated intracellular levels have often associated neurotoxicity, unclear if excitability features ALS are compensatory or pathological. Therefore, potentially contribute counteract neurodegeneration modulating fluxes, transiently selectively as well NMJ function, without increasing overall excitability. This further supports repurposing treatment other conditions characterized impairment, such aging.

Language: Английский

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Venom peptides regulating Ca2+ homeostasis: neuroprotective potential

Trends in Pharmacological Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

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