C-Jun N-terminal Kinase Promotes Stress Granule Assembly and Neurodegeneration in C9orf72-mediated ALS and FTD

Sahana, T. G.; Chase, Katherine Johnson; Liu, Feilin; Lloyd, Thomas E.; Rossoll, Wilfried; Zhang, Ke

doi:10.1101/2022.04.28.489917

Cited by 1 publication

(1 citation statement)

References 62 publications

(112 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mechanistic association between ALS and TBI has been investigated using animals including Drosophila [61,77] and rodent models of disease [78][79][80][81][82]. In some of these instances, TBI has been shown to cause stress granule formation, altered N/C transport dynamics, and TDP-43 mis-localization independent of genetic background [46,60,61,78,82], pathologies that have been documented in ALS patients [38,40,41,[83][84][85][86][87][88]. Moreover, while there are other reports of utilizing iPSC technologies to model TBI mechanisms in vitro [89][90][91][92] our approach represents the first to combine ALS patient specific iPSC-derived neurons with a traumatic injury infliction.…”

Section: Discussionmentioning

confidence: 99%

Traumatic injury causes selective degeneration and TDP-43 mislocalization in human iPSC-derivedC9orf72-associated ALS/FTD motor neurons

Martin,

Santacruz,

Mitevska

et al. 2024

Preprint

View full text Add to dashboard Cite

A hexanucleotide repeat expansion (HRE) inC9orf72is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, patients with the HRE exhibit a wide disparity in clinical presentation and age of symptom onset suggesting an interplay between genetic background and environmental stressors. Neurotrauma as a result of traumatic brain or spinal cord injury has been shown to increase the risk of ALS/FTD in epidemiological studies. Here, we combine patient-specific induced pluripotent stem cells (iPSCs) with a custom-built device to deliver biofidelic stretch trauma toC9orf72patient and isogenic control motor neurons (MNs)in vitro. We find that mutant but not control MNs exhibit selective degeneration after a single incident of severe trauma, which can be partially rescued by pretreatment with aC9orf72antisense oligonucleotide. A single incident of mild trauma does not cause degeneration but leads to cytoplasmic accumulation of TDP-43 inC9orf72MNs. This mislocalization, which only occurs briefly in isogenic controls, is eventually restored inC9orf72MNs after 6 days. Lastly, repeated mild trauma ablates the ability of patient MNs to recover. These findings highlight alterations in TDP-43 dynamics inC9orf72ALS/FTD patient MNs following traumatic injury and demonstrate that neurotrauma compounds neuropathology inC9orf72ALS/FTD. More broadly, our work establishes anin vitroplatform that can be used to interrogate the mechanistic interactions between ALS/FTD and neurotrauma.

show abstract