Heterogeneous nuclear ribonucleoprotein D - an understudied subfamily affected in sporadic TDP-43 proteinopathies

Despite the recognition that heterogeneous nuclear ribonucleoproteins (hnRNPs) modulate TDP-43 and can limit aberrant splicing events to compensate for TDP-43 loss, their role in TDP-43 proteinopathies remains poorly understood and studies in patient tissue are lacking. This study assesses seven heterogeneous nuclear ribonucleoproteins from the A/B, C, D and H subfamilies in two cortical regions implicated in early TDP-43 dysfunction versus late TDP-43 dysfunction in sporadic amyotrophic lateral sclerosis and/or frontotemporal lobar degeneration. Our results reveal significant nuclear loss of hnRNPD, hnRNPC and hnRNPA1 in the frontal cortex of frontotemporal lobar degeneration compared to amyotrophic lateral sclerosis but not in the motor cortical neurons or Betz cells of amyotrophic lateral sclerosis cases. Cytoplasmic co-occurrence was observed between hnRNPA1 and hnRNPC but not with phosphorylated TDP-43 (pTDP-43). Interestingly, nuclear hnRNPD loss associated with increasing cytoplasmic pTDP-43, highlighting an understudied subfamily in sporadic TDP-43 proteinopathies. In summary, this study identifies the nuclear loss of hnRNPD, C and A1 in a predilection brain region of TDP-43 in frontotemporal lobar degeneration compared to amyotrophic lateral sclerosis cases without significant pTDP-43 in this region. This highlights the need for further investigation into the involvement of these heterogeneous nuclear ribonucleoproteins in disease pathogenesis and potential to serve as modulatory targets and/or proximal markers of TDP-43 dysfunction in sporadic TDP-43 proteinopathies.