Divergent patterns of cytosolic TDP-43 and neuronal progranulin expression following axotomy: implications for TDP-43 in the physiological response to neuronal injury.
We have performed sciatic axotomies in adult C57BL/6 mice and observed TDP-43 and progranulin (PGRN) expression patterns over 28 days. TDP-43 expression was markedly upregulated in axotomized motor neurons, with prominent cytosolic immunoreactivity becoming maximal by post-injury day 7 and returning to baseline levels by post-injury day 28. Increased TDP-43 expression was confirmed by western blot. TDP-43 mRNA expression was also increased. This was inversely correlated with neuronal PGRN expression which was clearly reduced by day 7 with a return to baseline by post-injury day 28. In contrast, microglial PGRN expression was dramatically increased, and correlated with the inflammatory response to axotomy. Cytosolic TDP-43 colocalized with Staufen and TIA-1, markers for RNA transport and stress granules respectively. We did not observe colocalization of TDP-43 or PGRN with degradative granules (P-bodies) or activated caspase 3. These results indicate that TDP-43 expression is altered in response to neuronal injury and that normal expression is restored following recovery. These findings suggest that the upregulation of TDP-43 expression with prominent cytosolic localization in motor neurons injured by degenerative processes such as ALS may actually represent an appropriate response to neuronal injury.
Moisse
Katie
K
Molecular Brain Research Group, Robarts Research Institute, PO Box 5015, 100 Perth Drive, London ON, Canada N6A 5K8.
Volkening
Kathryn
K
Leystra-Lantz
Cheryl
C
Welch
Ian
I
Hill
Tracy
T
Strong
Michael J
MJ
D000704:Analysis of Variance; D000818:Animals; D019771:Axotomy; D053148:Caspase 3 / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000077155:Granulins; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D018613:Microscopy, Confocal; D009046:Motor Neurons / Q000378:metabolism*; D000077153:Progranulins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D012584:Sciatic Nerve / Q000293:injuries / Q000503:physiopathology; D013116:Spinal Cord / Q000378:metabolism*; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C492187:Stau1 protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3