Heterogeneous nuclear ribonucleoprotein E2 (HNRNPE2) is found as a component of TDP-43 aggregates specifically in the A and C pathological subtypes of frontotemporal lobar degeneration

Abstract

Transactive DNA binding protein (TDP-43) is the major component of the ubiquitin-positive protein aggregates seen in the majority of Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS) cases. TDP-43 belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family of proteins that are involved in the regulation of RNA transcription, splicing, transport and translation. There are a large number of hnRNPs, many of which have overlapping functions and often act cooperatively in RNA processing. Here we demonstrate that another hnRNP family member, hnRNP-E2, shows a striking accumulation within dystrophic neurites and cytoplasmic inclusions in the frontal cortex and hippocampus of a subset of FTLD-TDP cases. Further investigation showed this to be specific to cases of pathological subtype A and C, where hnRNP E2 was found to co-localize with 84.5% [WK1] of TDP-43 inclusions. hnRNP E2 inclusions were not seen in FTLD-TDP cases with the C9ORF72 expansion or in any other neurodegenerative disorders examined. The implications of this interaction with TDP-43 in inclusions in specific FTLD subtypes to neurodegenerative pathways suggest new avenues of research into FTLD-TDP.