Evidence of A Negative Feedback Network Between TDP-43 and miRNAs Dependent on TDP-43 Nuclear Localization

Abstract

TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein that is integral to RNA processing. Among these functions is a critical role in microRNA (miRNA) biogenesis through interactions with the DROSHA and DICER complexes. It has been previously shown that there is a general reduction in miRNA levels within the spinal cord and spinal motor neurons of amyotrophic lateral sclerosis (ALS) patients. In addition, the most common pathological feature of ALS is re-distribution of TDP-43 from the nucleus to the cytoplasm where it forms cytoplasmic inclusions. Among miRNAs dysregulated in ALS, several are known to regulate TDP-43 expression. In this study, we demonstrate that TDP-43 is in a regulatory negative feedback network with miR-181c-5p and miR-27b-3p that is dependent on its nuclear localization within HEK293T cells. Further, we show that cellular stress which induces a redistribution of TDP-43 from the nucleus to the cytoplasm correlates with the reduced production of miR-27b-3p and miR-181c-5p. This suggests that reduced nuclear TDP-43 disrupts a negative feedback network between itself and miRNAs. These findings provide a further understanding of altered miRNA biogenesis as a key pathogenic process in ALS.

Keywords: ALS; TDP-43; cell stress; miR-181c; miR-27b; microRNAs.