TDP-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model

Barton, Samantha K.; Magnani, Dario; James, Owen G; Livesey, Matthew R.; Selvaraj, Bhuvaneish T.; James, Owain T.; Perkins, Emma M.; Gregory, Jenna M; Cleary, Elaine M.; Ausems, C Rosanne M; Carter, Roderick N Carter; Vasistha, Navneet A.; Zhao, Chen; Burr, Karen; Story, David; Cardinali, Alessandra; Morton, Nicholas M.; Hardingham, Giles E.; Wyllie, David J. A.; Chandran, Siddharthan

doi:10.1093/braincomms/fcab255

Cited by 6 publications

(5 citation statements)

References 39 publications

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“…This model faithfully captures the neuronal loss and cytoplasmic accumulation characteristic of TDP43 proteinopathies. Beyond neurons, our model paves the way for inquiries into the roles of non-neuronal cells, such as oligodendrocytes and astrocytes, which also exhibit TDP43 proteinopathy, in contributing to neuronal dysfunction in a cell non-autonomous manner (Barton et al 2021; James et al 2022; Smethurst et al 2020; Licht-Murava et al 2023). We expect this model to not only enhance our understanding of ALS but also other TDP43 proteinopathies and accelerate efforts into developing therapies against these devastating neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Rapid and Inducible Mislocalization of Endogenous TDP43 in a Novel Human Model of Amyotrophic Lateral Sclerosis

Ganssauge,

Hawkins,

Namboori

et al. 2023

Preprint

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Transactive response DNA binding protein 43 kDa (TDP43) proteinopathy, characterized by the mislocalization and aggregation of TDP43, is a hallmark of several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). In this study, we describe the development of a new model of TDP43 proteinopathy using human induced pluripotent stem cell (iPSC)-derived neurons. Utilizing a genome engineering approach, we induced the mislocalization of endogenous TDP43 from the nucleus to the cytoplasm without mutating the TDP43 gene or using chemical stressors. Our model successfully recapitulates key pathological features of TDP43 proteinopathy, including neuronal loss, reduced neurite complexity, and cytoplasmic accumulation and aggregation of TDP43. Concurrently, the loss of nuclear TDP43 leads to splicing defects, while its cytoplasmic gain adversely affects microRNA expression. Strikingly, our observations suggest that TDP43 is capable of sustaining its own mislocalization, thereby perpetuating the proteinopathy. The development of this innovative model provides a valuable tool for the in-depth investigation of the consequences of TDP43 proteinopathy. We believe this will accelerate identification of potential therapeutic targets for the treatment of TDP43-associated neurodegenerative diseases including sporadic ALS.

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Section: Discussionmentioning

confidence: 99%

Rapid and Inducible Mislocalization of Endogenous TDP43 in a Novel Human Model of Amyotrophic Lateral Sclerosis

Ganssauge,

Hawkins,

Namboori

et al. 2023

Preprint

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“…The patient-derived hiPSC line harbouring the pathogenic TDP-43 G298S mutation was provided by Agnes Nishimura and Christopher Shaw (King’s College London), and originated from the group of Siddarthan Chandran (The University of Edinburgh). The TDP-43 G298S line was originally published in [ 33 ]. The donor provided written signed consent to donate their skin sample to derive iPSCs and their use was approved by the Ethics Committee from the King’s College Hospital, a national Medical Research Ethics Committee.…”

Section: Methodsmentioning

confidence: 99%

A scalable human iPSC-based neuromuscular disease model on suspended biobased elastomer nanofiber scaffolds

Cheesbrough,

Harley,

Riccio

et al. 2023

Biofabrication

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Many devastating neuromuscular diseases currently lack effective treatments. This is in part due to a lack of drug discovery platforms capable of assessing complex human neuromuscular disease phenotypes in a scalable manner. A major obstacle has been generating scaffolds to stabilise mature contractile myofibers in a multi-well assay format amenable to high content image analysis (HCI). This study describes the development of a scalable human iPSC-neuromuscular disease model, whereby suspended elastomer nanofibers support long-term stability, alignment, maturation, and repeated contractions of iPSC-myofibers, innervated by iPSC-motor neurons in 96-well assay plates. In this platform, optogenetic stimulation of the motor neurons elicits robust myofiber-contractions, providing a functional readout of neuromuscular transmission. Additionally, HCI provides rapid and automated quantification of axonal outgrowth, myofiber morphology, and neuromuscular synapse number and morphology. By incorporating amyotrophic lateral sclerosis (ALS)-related TDP-43G298S mutant motor neurons and CRISPR-corrected controls, key neuromuscular disease phenotypes are recapitulated, including weaker myofiber contractions, reduced axonal outgrowth, and reduced number of neuromuscular synapses. Treatment with a candidate ALS drug, the receptor-interacting protein kinase-1 (RIPK1)-inhibitor necrostatin-1, rescues these phenotypes in a dose-dependent manner, highlighting the potential of this platform to screen novel treatments for neuromuscular diseases.

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“…Patient-derived hiPSC line harbouring the pathogenic TDP-43 G298S mutation was provided by Christopher Shaw (King’s College London) and Siddarthan Chandran (The University of Edinburgh). The Line was originally published in: (Barton et al, 2021). Wildtype hESC H9 line was acquired from WiCell (Madison.…”

Section: Methodsmentioning

confidence: 99%

Pathogenic TDP-43 Disrupts Axon Initial Segment Structure and Neuronal Excitability in a Human iPSC Model of ALS

Harley

Neves

Riccio

et al. 2022

Preprint

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Dysregulated neuronal excitability is a hallmark of amyotrophic lateral sclerosis (ALS). We sought to investigate how functional changes to the axon initial segment (AIS), the site of action potential generation, could impact neuronal excitability in a human iPSC model of ALS. We found that early (6-week) ALS-related TDP-43G298S motor neurons showed an increase in the length of the AIS, relative to CRISPR-corrected controls. This was linked to neuronal hyperexcitability and increased spontaneous contractions of hiPSC-myofibers in compartmentalised neuromuscular co-cultures. In contrast late (10-week) TDP-43G298S motor neurons showed reduced AIS length and hypoexcitability. At a molecular level aberrant expression of the AIS master scaffolding protein Ankyrin-G, and the AIS-specific voltage-gated ion channels SCN1A (Nav1.1) and SCN8A (Nav1.6) mirrored these dynamic changes in excitability. Finally, at all stages, TDP-43G298S motor neurons showed compromised activity-dependent plasticity of the AIS, further contributing to abnormal excitability. Our results point toward the AIS as an important subcellular target driving changes to neuronal excitability in ALS.

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TDP-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model

Cited by 6 publications

References 39 publications

Rapid and Inducible Mislocalization of Endogenous TDP43 in a Novel Human Model of Amyotrophic Lateral Sclerosis

Rapid and Inducible Mislocalization of Endogenous TDP43 in a Novel Human Model of Amyotrophic Lateral Sclerosis

A scalable human iPSC-based neuromuscular disease model on suspended biobased elastomer nanofiber scaffolds

Pathogenic TDP-43 Disrupts Axon Initial Segment Structure and Neuronal Excitability in a Human iPSC Model of ALS

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