Abstract
BackgroundComponents of the innate immune complement system have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) specifically using hSOD1 transgenic animals; however, a comprehensive examination of complement expression in other transgenic ALS models has not been performed. This study therefore aimed to determine the expression of several key complement components and regulators in the lumbar spinal cord and tibialis anterior muscle of TDP-43Q331K mice during different disease ages.MethodsNon-transgenic, TDP-43WT and TDP-43Q331K mice were examined at three different ages of disease progression. Expression of complement components and their regulators were examined using real-time quantitative PCR and enzyme-linked immunosorbent assay. Localisation of terminal complement component receptor C5aR1 within the lumbar spinal cord was also investigated using immunohistochemistry.ResultsAltered levels of several major complement factors, including C5a, in the spinal cord and tibialis anterior muscle of TDP-43Q331K mice were observed as disease progressed, suggesting overall increased complement activation in TDP-43Q331K mice. C5aR1 increased during disease progression, with immuno-localisation demonstrating expression on motor neurons and expression on microglia surrounding the regions of motor neuron death. There was a strong negative linear relationship between spinal cord C1qB, C3 and C5aR1 mRNA levels with hind-limb grip strength.ConclusionsThese results indicate that similar to SOD1 transgenic animals, local complement activation and increased expression of C5aR1 may contribute to motor neuron death and neuromuscular junction denervation in the TDP-43Q331K mouse ALS model. This further validates C5aR1 as a potential therapeutic target for ALS.
Highlights
Components of the innate immune complement system have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) using hSOD1 transgenic animals; a comprehensive examination of complement expression in other transgenic ALS models has not been performed
Motor deficits in TDP-43Q331K mice correlate with increases in astrocytes and microglia during disease progression To monitor the decline in motor performance during disease onset and progression in TDP-43Q331K mice, we performed hind-limb grip strength tests in animals
We found that the decline in hind-limb grip strength in TDP-43Q331K mice closely correlated with the increase in immunoreactive area of astrocytes using immunofluorescence staining in the lumbar spinal cords at 10 months (~ 200% increase, n = 4, **P < 0.01; Fig. 1b, c) and 16 months (~ 380% increase, n = 4, ****P < 0.0001; Fig. 1b, c)
Summary
Components of the innate immune complement system have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) using hSOD1 transgenic animals; a comprehensive examination of complement expression in other transgenic ALS models has not been performed. This study aimed to determine the expression of several key complement components and regulators in the lumbar spinal cord and tibialis anterior muscle of TDP-43Q331K mice during different disease ages. Some of the genes that have been implicated in ALS include C9orf, VCP, FUS, SOD1 and TARDBP (TDP-43) [1,2,3,4,5]. Despite these differing aetiologies, sporadic and familial ALS patients are clinically and pathologically indistinguishable, suggesting that regardless of whether an ALS patient carries a known ALS mutation, or is sporadic, the underlying mechanism of motor neuron dysfunction is similar [6]. A key mediator of neuroinflammation is the chronic activation of the complement system, proposed to drive ALS disease progression [7]
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