TDP-43 dysregulation and neuromuscular junction disruption in amyotrophic lateral sclerosis

Lépine, Sarah; Castellanos-Montiel, María José; Durcan, Thomas M.

doi:10.1186/s40035-022-00331-z

Cited by 22 publications

(14 citation statements)

References 280 publications

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“…These results suggest both a morphological and functional defect in ALS NMJs. Our histological assessment and MEA electrophysiological recordings of NMJs derived from ALS patient iPSCs and respective controls recapitulate NMJ phenotypes that have been reported in the literature 3,40,53,54 . Because of the consistency and scalability of our method, as well as its proven sensitivity to detect relevant disease phenotypes within a week of motor neuron and skeletal muscle co-culture, our platform provides a new, promising avenue for high-throughput screening and potential therapeutic discoveries for ALS and other NMDs.…”

Section: Resultssupporting

confidence: 73%

Scalable, optically-responsive human neuromuscular junction model reveals convergent mechanisms of synaptic dysfunction in familial ALS

Chen,

Philippidou,

Brenha

et al. 2024

Preprint

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Neuromuscular junctions (NMJs) are specialized synapses that mediate communication between motor neurons and skeletal muscles and are essential for movement. The degeneration of this system can lead to symptoms observed in neuromuscular and motor neuron diseases. Studying these synapses and their degeneration has proven challenging. Prior NMJ studies heavily relied upon the use of mouse, chick, or isolated primary human cells, which have demonstrated limited fidelity for disease modeling. To enable the study of NMJ dysfunction and model genetic diseases, we, and others, have developed methods to generate human NMJs from pluripotent stem cells (PSCs), embryonic stem cells, and induced pluripotent stem cells. However, published studies have highlighted technical limitations associated with these complexin vitroNMJ models. In this study, we developed a robust PSC-derived motor neuron and skeletal muscle co-culture method, and demonstrated its sensitivity in modeling motor neuron disease. Our method spontaneously and reproducibly forms human NMJs. We developed multiwell-multielectrode array (MEA) parameters to quantify the activity of PSC-derived skeletal muscles, as well as measured the electrophysiological activity of functional human PSC-derived NMJs. We further leveraged our method to morphologically and functionally assess NMJs from the familial amyotrophic lateral sclerosis (fALS) PSCs,C9orf72hexanucleotide (G4C2)n repeat expansion (HRE),SOD1A5V, andTDP43G298S to define the reproducibility and sensitivity of our system. We observed a significant decrease in the numbers and activity of PSC-derived NMJs developed from the different ALS lines compared to their respective controls. Furthermore, we evaluated a therapeutic candidate undergoing clinical trials and observed a variant-dependent rescue of functionality of NMJs. Our newly developed method provides a platform for the systematic investigation of genetic causes of NMJ neurodegeneration and highlights the need for therapeutic avenues to consider patient genotype.

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Section: Resultssupporting

confidence: 73%

Scalable, optically-responsive human neuromuscular junction model reveals convergent mechanisms of synaptic dysfunction in familial ALS

Chen,

Philippidou,

Brenha

et al. 2024

Preprint

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“…Accumulating evidence suggests that TDP-43 is involved in synaptic functions, both at central and neuromuscular synapses (reviewed in (Gulino, 2023;Lépine et al, 2022;Ling, 2018)).…”

Section: Discussionmentioning

confidence: 99%

“…Accumulating evidence suggests that TDP-43 is involved in synaptic functions, both at central and neuromuscular synapses (reviewed in (Gulino, 2023; Lépine et al, 2022; Ling, 2018)). Pathologically altered TDP-43 has been shown to perturb the expression of synaptic genes in ALS mouse models and patients (Brown et al, 2022; Ma et al, 2022; Mishra et al, 2007; Polymenidou et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

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

Lépine

Nauleau-Javaudin

Deneault

et al. 2023

Preprint

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Cytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43 is a pathological hallmark of the motor neuron (MN) disease amyotrophic lateral sclerosis (ALS). Furthermore, while mutations in the TARDBP gene (encoding TDP-43) have been associated with ALS, the pathogenic consequences of these mutations remain poorly understood. Using CRISPR/Cas9, we engineered two homozygous knock-in iPSC lines carrying mutations in TARDBP encoding TDP-43A382Tand TDP-43G348C, two common yet understudied ALS TDP-43 variants. MNs differentiated from knock-in iPSCs had normal viability and displayed no significant changes in TDP-43 subcellular localization, phosphorylation, solubility, or aggregation compared with isogenic control MNs. However, our results highlight synaptic impairments in both TDP-43A382Tand TDP-43G348CMN cultures, as reflected in synapse abnormalities and alterations in spontaneous neuronal activity. Collectively, our findings argue that MN dysfunction precedes the occurrence of TDP-43 pathology and neurodegeneration in ALS, and further implicates synaptic and excitability defects in the pathobiology of this disease.

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“…Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) results in muscle denervation atrophy (Lepine et al, 2022). Therefore, it is crucial to use spatial transcriptomics to collect and examine changes in ALS gene expression in order to identify cellular subpopulations associated with each stage of the disease process and to investigate the underlying molecular mechanisms that cause and sustain the disease.…”

Section: Neurodegenerative Diseasementioning

confidence: 99%

Application of spatial transcriptome technologies to neurological diseases

Zhang²,

Chen³

et al. 2023

Front. Cell Dev. Biol.

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Spatial transcriptome technology acquires gene expression profiles while retaining spatial location information, it displays the gene expression properties of cells in situ. Through the investigation of cell heterogeneity, microenvironment, function, and cellular interactions, spatial transcriptome technology can deeply explore the pathogenic mechanisms of cell-type-specific responses and spatial localization in neurological diseases. The present article overviews spatial transcriptome technologies based on microdissection, in situ hybridization, in situ sequencing, in situ capture, and live cell labeling. Each technology is described along with its methods, detection throughput, spatial resolution, benefits, and drawbacks. Furthermore, their applications in neurodegenerative disease, neuropsychiatric illness, stroke and epilepsy are outlined. This information can be used to understand disease mechanisms, pick therapeutic targets, and establish biomarkers.

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TDP-43 dysregulation and neuromuscular junction disruption in amyotrophic lateral sclerosis

Cited by 22 publications

References 280 publications

Scalable, optically-responsive human neuromuscular junction model reveals convergent mechanisms of synaptic dysfunction in familial ALS

Scalable, optically-responsive human neuromuscular junction model reveals convergent mechanisms of synaptic dysfunction in familial ALS

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

Application of spatial transcriptome technologies to neurological diseases

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