Cytosolic TDP-43 expression following axotomy is associated with caspase 3 activation in NFL-/- 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(-/-)) mice and mutant SOD1(G93A) transgenic (mtSOD1(G93A)) mice aged 6 weeks, and observed TDP-43 and PGRN expression patterns in axotomized spinal motor neurons over 28 days.

The complement factor C5a receptor is upregulated in NFL-/- mouse motor neurons.

In NFL-/- mice, a model of motor neuron degeneration in ALS, degenerating spinal motor neurons express high levels of the receptor for the C5a anaphylatoxin (C5aR) early in the disease process. C5a is a potent in vitro neurotoxin for both Neuro2A and NGF-differentiated PC12 cells. While no interaction was observed between glutamate and C5a, both C5a and kainate upregulated the expression of activated C5aR.

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.

Transient middle cerebral artery occlusion induces microglial priming in the lumbar spinal cord: a novel model of neuroinflammation.

Background: Middle cerebral artery occlusion (MCAo) in mice results in a brain infarct, the volume of which depends on the length of occlusion. Following permanent occlusion, neuropathological changes - including a robust glial inflammatory response - also occur downstream of the infarct in the spinal cord.

Methods: We have performed short, transient MCAo in mice to induce penumbral damage spanning the motor cortex.

Innate immunity in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition in which motor neurons are selectively targeted. Although the underlying cause remains unclear, evidence suggests a role for innate immunity in disease pathogenesis. Neuroinflammation in areas of motor neuron loss is evident in presymptomatic mouse models of ALS and in human patients.