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Reversible induction of TDP-43 granules in cortical neurons after traumatic injury

Abstract : Traumatic brain injury (TBI) has been proposed as a risk factor for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). To determine whether TBI might trigger or exacerbate ALS-relevant pathology, we delivered a mild stab-wound injury to the motor cortex of three different ALS mouse models expressing mutations in SOD1, TDP-43 or FUS and scrutinized the effects on the formation of phospho-TDP-43 (pTDP-43) cytoplasmic granules. Stab-injury induced the formation of cytoplasmic TDP-43 granules in wt animals, peaking at 3dpi; a much larger response was seen in mutant TDP-43 mice, whose response peaked at 7dpi. The pTDP-43 granules did not colocalize with the stress markers TIAR-1 and FUS but colocalized with FMRP (35%) and with p62 (65%), suggesting their involvement in transport granules and their clearance by autophagy. A similar, albeit smaller effect, was seen in mutant FUS mice. In the SOD1G93A mouse model, neither increase in pTDP-43 granules nor in SOD1 aggregates were detected. In all cases, pTDP-43 granules were cleared and the number of pTDP-43-positive neurons returned to baseline by 40dpi. Neither injury-related neuronal loss nor motor performance or survival was significantly different in transgenic mice receiving injury vs sham mice. Thus, trauma can trigger ALS-related TDP-43 pathology, the extent of which is modulated by ALS-related mutations. However, the pathological findings prove reversible and do not affect disease progression and neuronal vulnerability.
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Contributor : Stéphane Dieterle Connect in order to contact the contributor
Submitted on : Tuesday, October 12, 2021 - 4:06:44 PM
Last modification on : Friday, April 8, 2022 - 12:28:02 PM
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Diana Wiesner, Lilla Tar, Birgit Linkus, Akila Chandrasekar, Florian Olde Heuvel, et al.. Reversible induction of TDP-43 granules in cortical neurons after traumatic injury. Experimental Neurology, Elsevier, 2018, 299 (Pt A), pp.15-25. ⟨10.1016/j.expneurol.2017.09.011⟩. ⟨inserm-03375256⟩



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