Elevated nuclear TDP-43 induces constitutive exon skipping
Journal
Molecular neurodegeneration
Journal Volume
19
Journal Issue
1
ISSN
1750-1326
Date Issued
2024-06-09
Author(s)
Carmen-Orozco, Rogger P
Tsao, William
Ye, Yingzhi
Sinha, Irika R
Trinh, Vickie T
Chung, William
Bowden, Kyra
Troncoso, Juan C
Blackshaw, Seth
Hayes, Lindsey R
Sun, Shuying
Wong, Philip C
Ling, Jonathan P
DOI
10.1186/s13024-024-00732-w
Abstract
Background: Cytoplasmic inclusions and loss of nuclear TDP-43 are key pathological features found in several neurodegenerative disorders, suggesting both gain- and loss-of-function mechanisms of disease. To study gain-of-function, TDP-43 overexpression has been used to generate in vitro and in vivo model systems. Methods: We analyzed RNA-seq datasets from mouse and human neurons overexpressing TDP-43 to explore species specific splicing patterns. We explored the dynamics between TDP-43 levels and exon repression in vitro. Furthermore we analyzed human brain samples and publicly available RNA datasets to explore the relationship between exon repression and disease. Results: Our study shows that excessive levels of nuclear TDP-43 protein lead to constitutive exon skipping that is largely species-specific. Furthermore, while aberrant exon skipping is detected in some human brains, it is not correlated with disease, unlike the incorporation of cryptic exons that occurs after loss of TDP-43. Conclusions: Our findings emphasize the need for caution in interpreting TDP-43 overexpression data and stress the importance of controlling for exon skipping when generating models of TDP-43 proteinopathy.
Publisher
BioMed Central Ltd
Description
Article number 45
Type
journal article