Martin, Eric JSantacruz, CitlallyMitevska, AngelaJones, Ian EKrishnan, GopinathGao, Fen-BiaoFinan, John DKiskinis, Evangelos2024-05-242024-05-242024-03-26Martin EJ, Santacruz C, Mitevska A, Jones IE, Krishnan G, Gao FB, Finan JD, Kiskinis E. Traumatic injury causes selective degeneration and TDP-43 mislocalization in human iPSC-derived C9orf72-associated ALS/FTD motor neurons. bioRxiv [Preprint]. 2024 Mar 26:2024.03.21.586073. doi: 10.1101/2024.03.21.586073. PMID: 38585915; PMCID: PMC10996466.10.1101/2024.03.21.58607338585915https://hdl.handle.net/20.500.14038/53376This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.A hexanucleotide repeat expansion (HRE) in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).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 to C9orf72 patient 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 a C9orf72 antisense oligonucleotide. A single incident of mild trauma does not cause degeneration but leads to cytoplasmic accumulation of TDP-43 in C9orf72 MNs. This mislocalization, which only occurs briefly in isogenic controls, is eventually restored in C9orf72 MNs after 6 days. Lastly, repeated mild trauma ablates the ability of patient MNs to recover. These findings highlight alterations in TDP-43 dynamics in C9orf72 ALS/FTD patient MNs following traumatic injury and demonstrate that neurotrauma compounds neuropathology in C9orf72 ALS/FTD. More broadly, our work establishes an in vitro platform that can be used to interrogate the mechanistic interactions between ALS/FTD and neurotrauma.enThe copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/C9orf72NeurotraumaTDP-43amyotrophic lateral sclerosis (ALS)frontotemporal dementia (FTD)iPSC modelsmotor neuronstraumatic brain injury (TBI)PreprintbioRxiv : the preprint server for biology