Importin alpha/beta and the tug of war to keep TDP-43 in solution: quo vadis?

The transactivation response-DNA binding protein of 43 kDa (TDP-43) is an aggregation-prone nucleic acid-binding protein linked to the etiology of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). These conditions feature the accumulation of insoluble TDP-43 aggregates in the neuronal cytoplasm that lead to cell death. The dynamics between cytoplasmic and nuclear TDP-43 are altered in the disease state where TDP-43 mislocalizes to the cytoplasm, disrupting Nuclear Pore Complexes (NPCs), and ultimately forming large fibrils stabilized by the C-terminal prion-like domain. Here, we review three emerging and poorly understood aspects of TDP-43 biology linked to its aggregation. First, how post-translational modifications in the proximity of TDP-43 N-terminal domain (NTD) promote aggregation. Second, how TDP-43 engages FG-nucleoporins in the NPC, disrupting the pore permeability and function. Third, how the importin alpha/beta heterodimer prevents TDP-43 aggregation, serving both as a nuclear import transporter and a cytoplasmic chaperone.