Human Induced Pluripotent Stem Cell-Derived TDP-43 Mutant Neurons Exhibit Consistent Functional Phenotypes Across Multiple Gene Edited Lines Despite Transcriptomic and Splicing Discrepancies
Autor: | Alec S. T. Smith, Changho Chun, Jennifer Hesson, Julie Mathieu, Paul N. Valdmanis, David L. Mack, Byung-Ok Choi, Deok-Ho Kim, Mark Bothwell |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
ALS (amyotrophic lateral sclerosis)
Mutation electrophysiologic analysis QH301-705.5 disease model Mutant Cell Biology Computational biology Biology medicine.disease_cause Phenotype Transcriptome Cell and Developmental Biology transcriptomics Genome editing RNA splicing medicine iPSC (induced pluripotent stem cell) Biology (General) Induced pluripotent stem cell Gene Developmental Biology Original Research |
Zdroj: | Frontiers in Cell and Developmental Biology, Vol 9 (2021) Frontiers in Cell and Developmental Biology |
Popis: | Gene editing technologies hold great potential to enhance our ability to model inheritable neurodegenerative diseases. Specifically, engineering multiple amyotrophic lateral sclerosis (ALS) mutations into isogenic cell populations facilitates determination of whether different causal mutations cause pathology via shared mechanisms, and provides the capacity to separate these mechanisms from genotype-specific effects. As gene-edited, cell-based models of human disease become more commonplace, there is an urgent need to verify that these models constitute consistent and accurate representations of native biology. Here, commercially sourced, induced pluripotent stem cell-derived motor neurons from Cellular Dynamics International, edited to express the ALS-relevant mutations TDP-43M337V and TDP-43Q331K were compared with in-house derived lines engineered to express the TDP-43Q331K mutation within the WTC11 background. Our results highlight electrophysiological and mitochondrial deficits in these edited cells that correlate with patient-derived cells, suggesting a consistent cellular phenotype arising from TDP-43 mutation. However, significant differences in the transcriptomic profiles and splicing behavior of the edited cells underscores the need for careful comparison of multiple lines when attempting to use these cells as a means to better understand the onset and progression of ALS in humans. |
Databáze: | OpenAIRE |
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