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

Abstract

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.