Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS/FTD

Abstract

TAR DNA binding protein 43 (TDP-43) pathology is a key feature of over 95% of amyotrophic lateral sclerosis (ALS) and nearly half of frontotemporal dementia (FTD) cases. The pathogenic mechanisms of TDP-43 dysfunction are poorly understood, however activation of cell stress pathways may contribute to pathogenesis. We therefore sought to identify which cell stress components are critical for driving disease onset and neurodegeneration in ALS/FTD. We studied the rNLS8 transgenic mouse model, which expresses human TDP-43 with a genetically-ablated nuclear localisation sequence within neurons of the brain and spinal cord resulting in cytoplasmic TDP-43 pathology and progressive motor dysfunction. Amongst numerous cell stress-related biological pathways profiled using qPCR arrays, several critical ISR effectors, including CCAAT/enhancer-binding homologous protein (Chop/Ddit3) and activating transcription factor 4 (Atf4), were upregulated in the cortex of rNLS8 mice prior to disease onset. This was accompanied by early up-regulation of anti-apoptotic gene Bcl2 and diverse pro-apoptotic genes including BH3-interacting domain death agonist (Bid). However, pro-apoptotic signalling predominated after onset of motor phenotypes. Notably, pro-apoptotic caspase-3 protein was elevated in the cortex of rNLS8 mice at later disease stages, suggesting that downstream activation of apoptosis drives neurodegeneration following failure of early protective responses. Unexpectedly, suppression of Chop in the brain and spinal cord using antisense oligonucleotide-mediated silencing had no effect on overall TDP-43 pathology or disease phenotypes in rNLS8 mice. Cytoplasmic TDP-43 accumulation therefore causes very early activation of ISR and both anti- and pro-apoptotic signalling that switches to predominant pro-apoptotic activation later in disease. These findings suggest that precise temporal modulation of cell stress and death pathways may be beneficial to protect against neurodegeneration in ALS and FTD.

Novelin vivoTDP-43 stress reporter models to accelerate drug development in ALS

“…Our reporter data demonstrates the early induction of oxidative stress, inflammation (pathways leading to Hmox1) and DNA damage (p21 reporter) in TDP-43 pathologies. However, other cellular stress responses have been associated with the accumulation of hTDP-43, including integrated stress response (27), endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) (28). Therefore, whether the pathways leading to Hmox1 or p21 expression are a cause or a consequence of TDP-43 related changes remains to be studied.…”

A stress-dependent TDP-43 SUMOylation program preserves neuronal function

“…Thus, mechanisms that may tip this physiological balance towards a pathogenic state likely underlie susceptibility to neurodegeneration. The cellular stress response is a critical pathway tightly linked to ALS/FTD and TDP-43 supported via genetic, experimental, and epidemiological evidence (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). On one hand, ALS/FTD-linked mutations disrupting various steps of the stress response pathways converge on the dysregulation of TDP-43 resulting in pathology (22-24, 29-32, 35).…”

“…The cellular stress response is a critical pathway tightly linked to ALS/FTD and TDP-43 supported via genetic, experimental, and epidemiological evidence( 22–35 ). On one hand, ALS/FTD-linked mutations disrupting various steps of the stress response pathways converge on the dysregulation of TDP-43 resulting in pathology( 22–24 , 29–32 , 35 ). On the other hand, exogenous insults such as head injuries, viral infections, and other exposures may confer susceptibility or precipitate ALS/FTD and can serve as pre-clinical models of TDP-43 proteinopathy( 5 , 10 , 11 , 36 ).…”