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

Diana Wiesner, Lilla Tar, Birgit Linkus, Akila Chandrasekar, Florian olde Heuvel, Luc Dupuis, William Tsao, Philip C. Wong, Albert Ludolph, Francesco Roselli

Research output: Research - peer-reviewArticle

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 3 dpi; a much larger response was seen in mutant TDP-43 mice, whose response peaked at 7 dpi. 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 40 dpi. 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.

LanguageEnglish (US)
Pages15-25
Number of pages11
JournalExperimental Neurology
Volume299
DOIs
StatePublished - Jan 1 2018

Fingerprint

Amyotrophic Lateral Sclerosis
Neurons
Wounds and Injuries
Pathology
Mutation
Traumatic Brain Injury
Stab Wounds
Cytoplasmic Granules
Autophagy
Motor Cortex
Neurodegenerative Diseases
Transgenic Mice
Disease Progression
1-(2'-tetrahydrothienyl) 5-fluorouracil

Keywords

  • ALS
  • Cortical injury
  • TDP-43

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

Cite this

Wiesner, D., Tar, L., Linkus, B., Chandrasekar, A., olde Heuvel, F., Dupuis, L., ... Roselli, F. (2018). Reversible induction of TDP-43 granules in cortical neurons after traumatic injury. Experimental Neurology, 299, 15-25. DOI: 10.1016/j.expneurol.2017.09.011

Reversible induction of TDP-43 granules in cortical neurons after traumatic injury. / Wiesner, Diana; Tar, Lilla; Linkus, Birgit; Chandrasekar, Akila; olde Heuvel, Florian; Dupuis, Luc; Tsao, William; Wong, Philip C.; Ludolph, Albert; Roselli, Francesco.

In: Experimental Neurology, Vol. 299, 01.01.2018, p. 15-25.

Research output: Research - peer-reviewArticle

Wiesner, D, Tar, L, Linkus, B, Chandrasekar, A, olde Heuvel, F, Dupuis, L, Tsao, W, Wong, PC, Ludolph, A & Roselli, F 2018, 'Reversible induction of TDP-43 granules in cortical neurons after traumatic injury' Experimental Neurology, vol 299, pp. 15-25. DOI: 10.1016/j.expneurol.2017.09.011
Wiesner D, Tar L, Linkus B, Chandrasekar A, olde Heuvel F, Dupuis L et al. Reversible induction of TDP-43 granules in cortical neurons after traumatic injury. Experimental Neurology. 2018 Jan 1;299:15-25. Available from, DOI: 10.1016/j.expneurol.2017.09.011
Wiesner, Diana ; Tar, Lilla ; Linkus, Birgit ; Chandrasekar, Akila ; olde Heuvel, Florian ; Dupuis, Luc ; Tsao, William ; Wong, Philip C. ; Ludolph, Albert ; Roselli, Francesco. / Reversible induction of TDP-43 granules in cortical neurons after traumatic injury. In: Experimental Neurology. 2018 ; Vol. 299. pp. 15-25
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