Changes in TDP-43 expression in development, aging, and in the neurofilament light protein knockout mouse

The transactive response DNA-binding protein 43 (TDP-43) has been identified as a neurofilament light (<i>NF-L</i>) mRNA binding protein. Abnormally increased levels of TDP-43 are detected in patients with amyotrophic lateral sclerosis as well as a downregulation of <i>NF-L</i> mRNA. However, links between NF-L and TDP-43 expression are unclear. In this study, we investigated whether the deficiency of NF-L protein can result in alterations in TDP-43 localisation or protein expression and whether this is altered with ageing. There was a significant increase in TDP-43 protein levels in the cortex and lumbar spinal cord in 12-month old NF-L knockout (KO) mice, compared to wild-type (WT) C57BL/6 mice. However, there was no difference in the phosphorylation of TDP-43 between WT and NF-L KO mice, nor abnormal mislocalisation of TDP-43 to the cytoplasm in NF-L KO animals. Our findings suggest that NF-L protein or mRNA may negatively affect the expression of TDP-43 in the central nervous system. However, altered phosphorylation of TDP-43 may be more highly associated with ageing than levels of TDP-43 expression.