Systemic dysregulation of TDP-43 binding microRNAs in amyotrophic lateral sclerosis

Abstract

BACKGROUND A pathological hallmark of most amyotrophic lateral sclerosis (ALS) cases are intracellular aggregates of the protein TDP-43. The pathophysiological relevance of TDP-43 is underlined by familial ALS cases caused by TDP-43 mutations. TDP-43 is involved in processing of both coding RNAs and microRNAs, which are key epigenetic regulators of transcriptome plasticity and suspected to contribute to neurological diseases. We therefore asked whether the TDP-43 binding microRNAs recently identified in cell lines are also dysregulated in ALS patients. We compared their abundance in cerebrospinal fluid (CSF), serum and immortalized lymphoblast cell lines (LCLs) derived from ALS patients and healthy controls. RESULTS We found that expression levels of 5 out of 9 TDP-43 binding microRNAs were altered in the CSF and serum of sporadic ALS cases. The differentially regulated serum microRNAs together with a poor correlation between CSF and serum levels indicate a systemic dysregulation of microRNA abundance independent from the CSF compartment, in line with the ubiquitous expression of TDP-43. The most strongly regulated microRNAs could be confirmed in LCLs from genetically defined ALS patients. While dysregulation of miR-143-5p/3p seems to be a common feature of ALS pathology, downregulation of miR-132-5p/3p and miR-574-5p/3p was evident in sporadic, TARDBP, FUS and C9ORF72, but not SOD1 mutant patients. This parallels the TDP-43 pathology found in most ALS cases, but usually not in patients with SOD1 mutation. CONCLUSIONS We thus report a systemic and genotype-dependent dysregulation of TDP-43 binding microRNAs in human biomaterial that might reflect an easily accessible biological measure of TDP-43 dysfunction. Furthermore we suggest an independent regulation of TDP-43 binding microRNAs in the serum and CSF compartment as well as a generally low transition of microRNAs across the blood-cerebrospinal fluid barrier.