Traumatic injury causes selective degeneration and TDP-43 mislocalization in human iPSC-derived C9orf72 -associated ALS/FTD motor neurons.

Autor:	Martin EJ; The Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA., Santacruz C; Department of Mechanical and Industrial Engineering, University of Illinois at Chicago, Chicago, IL, USA., Mitevska A; Department of Mechanical and Industrial Engineering, University of Illinois at Chicago, Chicago, IL, USA., Jones IE; Department of Mechanical and Industrial Engineering, University of Illinois at Chicago, Chicago, IL, USA., Krishnan G; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA., Gao FB; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA., Finan JD; Department of Mechanical and Industrial Engineering, University of Illinois at Chicago, Chicago, IL, USA., Kiskinis E; The Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.; Simpson Querrey Institute, Northwestern University, Chicago, Illinois 60611, USA.; Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Mar 26. Date of Electronic Publication: 2024 Mar 26.
DOI:	10.1101/2024.03.21.586073
Abstrakt:	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. Competing Interests: DECLARATION OF INTERESTS E.K is a cofounder of NeuronGrow, SAB member of Axion Biosystems, ResQ Biotech and Synapticure and a consultant for Confluence Therapeutics; named companies were not involved in this project. The authors declare no other competing interests.
Databáze:	MEDLINE
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