Modeling of TDP-43 proteinopathy by chronic oxidative stress identifies rapamycin as beneficial in ALS patient-derived 2D and 3D iPSC models
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View abstract on PubMed
Summary
This summary is machine-generated.Researchers developed new models of Amyotrophic Lateral Sclerosis (ALS) by inducing oxidative stress. Rapamycin effectively prevented TDP-43 proteinopathy and restored splicing activity in these models, offering hope for ALS therapy development.
Area Of Science
- Neuroscience
- Molecular Biology
- Cell Biology
Background
- Amyotrophic Lateral Sclerosis (ALS) is characterized by TDP-43 proteinopathy, involving cytoplasmic aggregation and loss of nuclear splicing activity.
- Existing experimental models have limitations in fully recapitulating TDP-43 gain and loss of function mechanisms.
- Oxidative stress is implicated in neurodegenerative processes, but its specific impact on TDP-43 splicing in disease models requires further elucidation.
Purpose Of The Study
- To establish and validate human cell models that mimic TDP-43 proteinopathy, including both cytoplasmic aggregation and nuclear splicing defects.
- To investigate the effect of chronic oxidative insult on TDP-43 function and related cellular pathways like autophagy and senescence.
- To screen for potential therapeutic agents, specifically autophagy-promoting drugs, capable of ameliorating TDP-43 pathology in vitro.
Main Methods
- Induction of chronic oxidative stress using sodium arsenite (ARS) in human neuroblastoma cells, patient-derived fibroblasts, and induced pluripotent stem cell-derived motor neurons (iPSC-MNs).
- Assessment of TDP-43 localization, stress granule (SG) formation, and splicing activity of target genes (e.g., UNC13A, POLDIP3).
- Evaluation of autophagy and senescence markers, followed by drug screening with rapamycin, lithium carbonate, and metformin.
Main Results
- Chronic ARS exposure induced TDP-43 cytoplasmic mislocalization, SG formation, and defective splicing of target genes in neuroblastoma cells, fibroblasts, and iPSC-MNs.
- Dysregulation of autophagy and senescence markers was observed alongside TDP-43 pathology.
- Rapamycin effectively prevented ARS-induced loss of TDP-43 splicing activity and reduced TDP-43 aggregation in various cell models, including a 3D brain organoid model.
Conclusions
- Established human cell and 3D organoid models effectively recapitulate key aspects of TDP-43 proteinopathy, including gain and loss of function.
- Chronic oxidative stress is a viable method to induce these pathological features in vitro.
- Rapamycin demonstrates therapeutic potential by ameliorating TDP-43 pathology, highlighting its promise for future ALS drug screening and development.
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