TDP-43 protein interactome informs about perturbed canonical pathways and may help develop personalized medicine approaches for patients with TDP-43 pathology

Abstract

Transactive response DNA binding protein of 43 kDa (TDP-43) pathology is a common proteinopathy observed among a broad spectrum of patients with neurodegenerative disease, regardless of the mutation. This suggests that protein-protein interactions of TDP-43 with other proteins may in part be responsible for the pathology. To gain better insights, we investigated TDP-43-binding proteins in each domain and correlated these interactions with canonical pathways. These investigations revealed key cellular events that are involved and are important at each domain and suggested previously identified compounds to modulate key aspects of these canonical pathways. Our approach proposes that personalized medicine approaches, which focus on perturbed cellular mechanisms would be feasible in the near future.

Keywords: TDP-43; canonical pathways; personalized medicine; precision medicine; protein–protein interactions.

FIGURE 1

The domain structure of TDP-43 protein and its 3D conformation, showing the location of each canonical domain. Additionally, a linear representation of the TDP-43 protein’s amino acid sequence is shown.

FIGURE 2

(a) Graphical representation of the sum of the predicted interaction residues at each amino acid position in the TDP-43 protein. (b) Linear representation of TDP-43 amino acid sequence and distinct domains. Additionally, an overlay of previously identified patient mutations is shown. (c) List of interaction partners that show a predicted association with that respective domain.

FIGURE 3

Glycine rich domain (GRD) interaction partner analysis. (a) Circular representation of GRD binding partner’s association between type of location. (b) Bar graphs of canonical pathways associated with GRD interaction partners [−P(log value)] and their overlap (ratio, yellow line). (c) Image of eIF2 signaling pathway, representing the extent of GRD protein involvement.

FIGURE 4

RNA recognition motif 1 (RRM1) interaction partner analysis. (a) Circular representation of RRM1 binding partner’s association between type of location. (b) Bar graphs of canonical pathways associated with RRM1 interaction partners [−P(log value)] and their overlap (ratio, yellow line). (c) Image of regulation of the eIF4 and p70S6K signaling pathways, representing the extent of RRM1 protein involvement.

FIGURE 5

RNA recognition motif 2 (RRM2) interaction partner analysis. (a) Circular representation of RRM2 binding partner’s association between type of location. (b) Bar graphs of canonical pathways associated with RRM2 interaction partners [−P(log value)] and their overlap (ratio, yellow line). (c) Image of the CSDE1 signaling pathway, representing the extent of RRM2 protein involvement.

FIGURE 6

Nuclear localization signal (NLS) domain interaction partner analysis. (a) Circular representation of NLS binding partner’s association between type of location. (b) Bar graphs of canonical pathways associated with NLS interaction partners [−P(log value)] and their overlap (ratio, yellow line). (c) Image of microRNA biogenesis signaling pathway, representing the extent of NLS protein involvement.