RRC ID 54185
Author Yahara M, Kitamura A, Kinjo M.
Title U6 snRNA expression prevents toxicity in TDP-43-knockdown cells.
Journal PLoS One
Abstract Depletion of amyotrophic lateral sclerosis (ALS)-associated transactivation response (TAR) RNA/DNA-binding protein 43 kDa (TDP-43) alters splicing efficiency of multiple transcripts and results in neuronal cell death. TDP-43 depletion can also disturb expression levels of small nuclear RNAs (snRNAs) as spliceosomal components. Despite this knowledge, the relationship between cell death and alteration of snRNA expression during TDP-43 depletion remains unclear. Here, we knocked down TDP-43 in murine neuroblastoma Neuro2A cells and found a time lag between efficient TDP-43 depletion and appearance of cell death, suggesting that several mechanisms mediate between these two events. The amount of U6 snRNA was significantly decreased during TDP-43 depletion prior to increase of cell death, whereas that of U1, U2, and U4 snRNAs was not. Downregulation of U6 snRNA led to cell death, whereas transient exogenous expression of U6 snRNA counteracted the effect of TDP-43 knockdown on cell death, and slightly decreased the mis-splicing rate of Dnajc5 and Sortilin 1 transcripts, which are assisted by TDP-43. These results suggest that regulation of the U6 snRNA expression level by TDP-43 is a key factor in the increase in cell death upon TDP-43 loss-of-function.
Volume 12(11)
Pages e0187813
Published 2017-11-10
DOI 10.1371/journal.pone.0187813
PII PONE-D-17-20742
PMID 29125873
PMC PMC5681290
MeSH Animals Apoptosis Cell Line, Tumor DNA-Binding Proteins / genetics* Down-Regulation Gene Knockout Techniques Mice RNA, Small Nuclear / genetics*
IF 2.74
Times Cited 4
Resource
DNA material pSuperior.neo-U6snRNA (RDB16712)