Unknown

Dataset Information

0

TDP-43 knockdown causes innate immune activation via protein kinase R in astrocytes.


ABSTRACT: TAR-DNA binding protein 43 (TDP-43) is a multifunctional RNA binding protein directly implicated in the etiology of amyotrophic lateral sclerosis (ALS). Previous studies have demonstrated that loss of TDP-43 function leads to intracellular accumulation of non-coding repetitive element transcripts and double-stranded RNA (dsRNA). These events could cause immune activation and contribute to the neuroinflammation observed in ALS, but this possibility has not been investigated. Here, we knock down TDP-43 in primary rat astrocytes via siRNA, and we use RNA-seq, immunofluorescence, and immunoblotting to show that this results in: 1) accumulation of repetitive element transcripts and dsRNA; and 2) pro-inflammatory gene and protein expression consistent with innate immune signaling and astrocyte activation. We also show that both chemical inhibition and siRNA knockdown of protein kinase R (PKR), a dsRNA-activated kinase implicated in the innate immune response, block the expression of all activation markers assayed. Based on these findings, we suggest that intracellular accumulation of endogenous dsRNA may be a novel and important mechanism underlying the pathogenesis of ALS (and perhaps other neurodegenerative diseases), and that PKR inhibitors may have the potential to prevent reactive astrocytosis in ALS.

SUBMITTER: LaRocca TJ 

PROVIDER: S-EPMC6834892 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

altmetric image

Publications

TDP-43 knockdown causes innate immune activation via protein kinase R in astrocytes.

LaRocca Thomas J TJ   Mariani Andrea A   Watkins Linda R LR   Link Christopher D CD  

Neurobiology of disease 20190621


TAR-DNA binding protein 43 (TDP-43) is a multifunctional RNA binding protein directly implicated in the etiology of amyotrophic lateral sclerosis (ALS). Previous studies have demonstrated that loss of TDP-43 function leads to intracellular accumulation of non-coding repetitive element transcripts and double-stranded RNA (dsRNA). These events could cause immune activation and contribute to the neuroinflammation observed in ALS, but this possibility has not been investigated. Here, we knock down T  ...[more]

Similar Datasets

| S-EPMC7556969 | biostudies-literature
2019-08-09 | GSE135611 | GEO
| S-EPMC8003223 | biostudies-literature
| S-EPMC10411944 | biostudies-literature
2011-03-25 | E-MTAB-527 | biostudies-arrayexpress
| S-EPMC5036055 | biostudies-literature
| PRJNA559433 | ENA
| S-EPMC3981181 | biostudies-literature
| S-EPMC4066372 | biostudies-literature
| S-EPMC5681290 | biostudies-literature