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

TDP-43 knockdown causes innate immune activation via protein kinase R in astrocytes.
Neurobiol Dis. 2019 Jun 20;:104514
Authors: LaRocca TJ, Mariani A, Watkins LR, Link CD
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 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 rea...

Source: Neurobiology of Disease - June 19, 2019 Category: Neurology Authors: LaRocca TJ, Mariani A, Watkins LR, Link CD Tags: Neurobiol Dis Source Type: research