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RSS FeedsIJMS, Vol. 23, Pages 14769: Understanding In Vitro Pathways to Drug Discovery for TDP-43 Proteinopathies (International Journal of Molecular Sciences)

 
 

25 november 2022 16:24:07

 
IJMS, Vol. 23, Pages 14769: Understanding In Vitro Pathways to Drug Discovery for TDP-43 Proteinopathies (International Journal of Molecular Sciences)
 


The use of cellular models is a common means to investigate the potency of therapeutics in pre-clinical drug discovery. However, there is currently no consensus on which model most accurately replicates key aspects of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) pathology, such as accumulation of insoluble, cytoplasmic transactive response DNA-binding protein (TDP-43) and the formation of insoluble stress granules. Given this, we characterised two TDP-43 proteinopathy cellular models that were based on different aetiologies of disease. The first was a sodium arsenite-induced chronic oxidative stress model and the second expressed a disease-relevant TDP-43 mutation (TDP-43 M337V). The sodium arsenite model displayed most aspects of TDP-43, stress granule and ubiquitin pathology seen in human ALS/FTD donor tissue, whereas the mutant cell line only modelled some aspects. When these two cellular models were exposed to small molecule chemical probes, different effects were observed across the two models. For example, a previously disclosed sulfonamide compound decreased cytoplasmic TDP-43 and increased soluble levels of stress granule marker TIA-1 in the cellular stress model without impacting these levels in the mutant cell line. This study highlights the challenges of using cellular models in lead development during drug discovery for ALS and FTD and reinforces the need to perform assessments of novel therapeutics across a variety of cell lines and aetiological models.


 
94 viewsCategory: Biochemistry, Biophysics, Molecular Biology
 
IJMS, Vol. 23, Pages 14767: Plethora of Non-Covalent Interactions in Coordination and Organometallic Chemistry Are Modern Smart Tool for Materials Science, Catalysis, and Drugs Design (International Journal of Molecular Sciences)
IJMS, Vol. 23, Pages 14770: Cancer Stem Cell Formation Induced and Regulated by Extracellular ATP and Stanniocalcin-1 in Human Lung Cancer Cells and Tumors (International Journal of Molecular Sciences)
 
 
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