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Pathological Comparison of TDP-43 Between Motor Neurons and Interneurons Expressed by a Tetracycline Repressor System on the Mouse Artificial Chromosome
[ABSTRACT] [Background] Cytoplasmic mislocalization of TAR-DNA binding protein of 43 kDa (TDP-43) is a major hallmark of amyotrophic lateral sclerosis (ALS). TDP-43 aggregation is detected in the cortical and spinal motor neurons in most ALS cases; however, pathological mechanism of this mislocalize...
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Published in: | YONAGO ACTA MEDICA 2023, Vol.66 (1), p.24-35 |
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Main Authors: | , , , |
Format: | Article |
Language: | jpn ; eng |
Subjects: | |
Online Access: | Get full text |
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Summary: | [ABSTRACT] [Background] Cytoplasmic mislocalization of TAR-DNA binding protein of 43 kDa (TDP-43) is a major hallmark of amyotrophic lateral sclerosis (ALS). TDP-43 aggregation is detected in the cortical and spinal motor neurons in most ALS cases; however, pathological mechanism of this mislocalized TDP-43 remains unknown. [Methods] We generated a tetracycline-inducible TDP-43 A315T system on a mouse artificial chromosome (MAC) vector to avoid transgene-insertional mutagenesis, established a mouse embryonic stem (ES) cell line holding this MAC vector system, and investigated whether overexpressed exogenous TDP-43 A315T was mislocalized in the cytoplasm of the ES cell-derived neurons and triggered the neurotoxic effects on these cells. [Results] Inducible TDP-43 A315T system was successfully loaded onto the MAC and introduced into the mouse ES cells. These ES cells could differentiate into motor neurons and interneurons. Overexpression of TDP-43 A315T by addition of doxycycline in both neurons resulted in mislocalization to cytoplasm. Mislocalized TDP-43 caused cell death of motor neurons, but not interneurons. [Conclusion] Vulnerability to cytoplasmic mislocalized TDP-43 is selective on neuronal types, whereas mislocalization of overexpressed TDP-43 occurs in even insusceptible neurons. This inducible gene expression system using MAC remains useful for providing critical insights into appearance of TDP-43 pathology. |
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ISSN: | 0513-5710 1346-8049 |
DOI: | 10.33160/yam.2023.02.004 |