Cytosolic TDP-43 expression following axotomy is associated with caspase 3 activation in NFL super(-) super(/) super(-) mice: Support for a role for TDP-43 in the physiological response to neuronal injury

TAR DNA binding protein (TDP-43) mislocalization has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). We have recently reported that TDP-43 and PGRN expression is altered in response to axotomy in C57BL6 mice and that normal expression is restored following recovery. We have performed axotomies in two different presymptomatic models of motor neuron degeneration, low molecular weight neurofilament knockout (NFL super(-) super(/) super(-)) mice and mutant SOD1 super(G) super(9) super(3) super(A) transgenic (mtSOD1 super(G) super(9) super(3) super(A)) mice aged 6 weeks, and observed TDP-43 and PGRN expression patterns in axotomized spinal motor neurons over 28 days. In contrast to both C57BL6 mice and mtSOD1 super(G) super(9) super(3) super(A) mice, behavioural deficits in NFL super(-) super(/) super(-) mice were sustained. We did not observe differences in TDP-43 or PGRN expression between C57BL6 mice and mtSOD1 super(G) super(9) super(3) super(A) mice throughout the observation period. However, compared to C57BL6 mice and mtSOD1 super(G) super(9) super(3) super(A) mice, NFL super(-) super(/) super(-) mice exhibited late upregulation of cytosolic TDP-43 expression and persistent downregulation of neuronal PGRN expression accompanied by caspase 3 activation on post-injury day 28. By post-injury day 42, no cytosolic TDP-43-positive neurons remained in NFL super(-) super(/) super(-) mice, suggesting that they had undergone apoptotic cell death. These findings suggest that whereas TDP-43 expression is normally upregulated transiently following axotomy, in the absence of NFL this response is delayed and associated with caspase 3 activation and neuronal death. These results further support that TDP-43 is involved in neurofilament mRNA metabolism and transport, and provide insight into the pathogenesis of motor neuron death in ALS in which NFL mRNA levels are selectively suppressed.