Nup62 is recruited to pathological condensates and promotes TDP-43 insolubility in C9orf72 and sporadic ALS/FTLD.

Abstract

Amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD) share clinical, neuropathological, and genetic features. This includes common genetic disease-causing mutations such as the expanded G4C2 repeat in the C9orf72 gene (C9-ALS/FTLD) and cytoplasmic and insoluble protein depositions of the TDP-43 in degenerating regions of the brain and spinal cord. Proposed mechanisms of toxicity in C9-ALS/FTLD are the production of repeat expansion transcripts and their dipeptide repeat proteins (DPRs) products which are hypothesized to drive nucleocytoplasmic transport defects. The nuclear pore complex (NPC) regulates nucleocytoplasmic trafficking by creating a selectivity and permeability barrier comprised of phenylalanine glycine nucleoporins (FG nups). However, the relationship between FG nups and TDP-43 pathology remains elusive. Here, we define two mechanisms through which TDP-43 promotes Nup62 nuclear depletion and cytoplasmic in C9-ALS/FTLD and sALS/FTLD. In C9-ALS/FTLD, poly-GR initiates the formation of TDP-43 containing stress granules (SGs) that trigger the nuclear loss and recruitment of Nup62 in vitro and in vivo. When colocalized, cytoplasmic TDP-43:Nup62 assemblies mature into insoluble inclusions through an interaction within the TDP-43 nuclear localization sequence (NLS) suggesting Nup62 promotes deleterious phase transitions. Absent of poly-GR, aberrant TDP-43 phase transitions in the cytoplasm recruits and mislocalizes Nup62 into pathological inclusions. The result of these cytoplasmic Nup62 and TDP-43 interactions are pathological and insoluble TDP-43:Nup62 assemblies that are observed in C9-ALS/FTLD and sALS/FTLD CNS tissue.

Multivalent GU-rich oligonucleotides sequester TDP-43 in the nucleus by inducing high molecular weight RNP complexes

“…[10][11][12] Notably, TDP-43 binds its own 3'-UTR at a sequence termed Clip34nt to autoregulate its expression. 10,13 Binding up to one-third of the mammalian transcriptome, TDP-43 functions prolifically in the regulation of RNA processing, including alternative splicing, 10,11 the repression of cryptic exons, 12,14,15 alternative polyadenylation, [16][17][18][19][20] and the processing of miRNA 21 and lncRNAs, including long interspersed nuclear elements (LINEs). 22 The nucleocytoplasmic localization of TDP-43 is regulated by a dynamic balance between nuclear import and export.…”