TY - JOUR
T1 - Reversible induction of TDP-43 granules in cortical neurons after traumatic injury
AU - Wiesner, Diana
AU - Tar, Lilla
AU - Linkus, Birgit
AU - Chandrasekar, Akila
AU - olde Heuvel, Florian
AU - Dupuis, Luc
AU - Tsao, William
AU - Wong, Philip C.
AU - Ludolph, Albert
AU - Roselli, Francesco
N1 - Funding Information:
F.R. is member of the Ulm Trauma Research Center and it is supported by DFG ( SFB1149-B05 ) in the “Danger Response, Disturbance Factors and Regenerative Potential after Acute Trauma” Collaborative Research Center (SFB1149), by the ERANET-NEURON “External insults to the CNS” program as part of the MICRONET consortium and by the Baustein Program of the Ulm University Medical Faculty ( LSBN108 ).
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2018/1
Y1 - 2018/1
N2 - 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.
AB - 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.
KW - ALS
KW - Cortical injury
KW - TDP-43
UR - http://www.scopus.com/inward/record.url?scp=85029699014&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85029699014&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2017.09.011
DO - 10.1016/j.expneurol.2017.09.011
M3 - Article
C2 - 28941811
AN - SCOPUS:85029699014
SN - 0014-4886
VL - 299
SP - 15
EP - 25
JO - Experimental Neurology
JF - Experimental Neurology
ER -