Importin α/β and the tug of war to keep TDP‐43 in solution: quo vadis?. (17th October 2022)

• Record Type: Journal Article
• Authors: Doll, Steven G.; Cingolani, Gino
• Is Part Of: BioEssays. Volume 44:Number 12(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-10-17
• Subjects: TDP‐43 -- NTD -- importin α/β -- FG‐nucleoporins -- protein aggregation -- neurodegeneration; Molecular biology -- Periodicals; Cytology -- Periodicals; Developmental biology -- Periodicals; 572.8
• DOI: 10.1002/bies.202200181
• Languages: English
• ISSNs: 0265-9247

Abstract

Abstract: 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 α/β heterodimer prevents TDP‐43 aggregation, serving both as a nuclear import transporter and a cytoplasmic chaperone. Abstract : Mislocalization of TDP‐43 leads to insoluble cytoplasmic aggregates and disruption of the Nuclear Pore Complex, commonly found in sporadic ALS. Here we review new trends in TDP‐43 biology, focusing on the importin α/β heterodimer as an import receptor and cytoplasmic chaperone.