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.