GSE157714
TDP-43 represses a cryptic exon in Schwann cells to ensure rapid saltatory conduction
A pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia is the aggregation of TDP-43. While extensive exploration into the function of TDP-43 has focused entirely in the central nervous system (CNS), the implications in physiology and pathology of the peripheral nervous system (PNS) have long been overlooked. Herein, we demonstrate that deletion of TDP-43 in Schwann cells results in a 50% reduction in peripheral nerve conduction velocity, without any obvious alterations to peripheral compact myelin. Compromised insulatory function of myelin was due to the complete loss of paranodal axoglial junctions flanking the nodes of Ranvier. By contrast, the paranodal junctions in the CNS oligodendrocytes are unaltered upon deletion of TDP-43. Mechanistically, TDP-43 binds directly to Nfasc mRNA, which encodes neurofascin, a key cell adhesion molecule essential for establishing paranodal junctions. TDP-43 binding sites overlap with a cryptic exon of Nfasc such that loss of TDP-43 leads to the retention of this cryptic exon with a premature stop codon, a prerequisite for nonsense-mediated decay. Thus, TDP-43 is required for the proper assembly of nodes of Ranvier that is essential for saltatory conduction by suppressing the cryptic exon in the Nfasc mRNA of the Schwann cells. Our findings indicate a direct involvement of TDP-43 in normal PNS function and suggest that PNS-autonomous dysfunction in saltatory conduction may contribute to TDP-43 proteinopathies. Overall design: Bulk RNA-Seq of sciatic nerve tissue of 21-day old mice with TDP-43 deleted in Schwann cells.