NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility

Abstract

A G4C2 hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of ALS and FTLD (C9-ALS/FTLD) with cytoplasmic TDP-43 inclusions observed in regions of neurodegeneration. The accumulation of repetitive RNAs and dipeptide repeat protein (DPR) are two proposed mechanisms of toxicity in C9-ALS/FTLD and linked to impaired nucleocytoplasmic transport. Nucleocytoplasmic transport is regulated by the phenylalanine-glycine nucleoporins (FG nups) that comprise the nuclear pore complex (NPC) permeability barrier. However, the relationship between FG nups and TDP-43 pathology remains elusive. Our studies show that nuclear depletion and cytoplasmic mislocalization of one FG nup, NUP62, is linked to TDP-43 mislocalization in C9-ALS/FTLD iPSC neurons. Poly-glycine arginine (GR) DPR accumulation initiates the formation of cytoplasmic RNA granules that recruit NUP62 and TDP-43. Cytoplasmic NUP62 and TDP-43 interactions promotes their insolubility and NUP62:TDP-43 inclusions are frequently found in C9orf72 ALS/FTLD as well as sporadic ALS/FTLD postmortem CNS tissue. Our findings indicate NUP62 cytoplasmic mislocalization contributes to TDP-43 proteinopathy in ALS/FTLD.

Cytoplasmic nucleoporin foci are stress-sensitive, non-essential condensates in C. elegans

“…Nup98 is highly cohesive due to its extreme hydrophobicity and interacts with Nups from multiple subcomplexes (Griffis et al, 2003; Onischenko et al, 2017; Yoshida et al, 2011); therefore Nup98 may be uniquely capable of seeding toxic condensates. Our findings are consistent with recent studies reporting that cytoplasmic FG-Nups drive aggregation of TDP-43 in both ALS/FTLD and following traumatic brain injury (Anderson et al, 2021; Gleixner et al, 2022).…”

“…Our findings are consistent with recent studies reporting that cytoplasmic FG-Nups drive aggregation of TDP-43 in both ALS/FTLD and following traumatic brain injury (Anderson et al, 2021;Gleixner et al, 2022).…”

“…Nups are also frequently enriched in pathological cytoplasmic inclusions that are hallmarks of neurodegenerative disease (Chandra and Lusk, 2022; Fallini et al, 2020; Hutten and Dormann, 2020), leading to the proposal that Nups become sequestered and depleted from nuclear pores under disease conditions (Gasset-Rosa et al, 2019; Zhang et al, 2018). Condensation of FG-Nup fusion oncogenes contributes to certain cancers (Chandra et al, 2022; Terlecki-Zaniewicz et al, 2021; Zhou and Yang, 2014), and recent studies have found that cytoplasmic FG-Nups drive aggregation of TDP-43 in ALS/FTLD and following traumatic brain injury (Anderson et al, 2021; Gleixner et al, 2022). Together, these observations raise the possibility that ectopic condensation of FG-Nups may drive protein aggregation and disease progression.…”

Aging RNA granule dynamics in neurodegeneration

“…In addition, recent work has shown that sex chromosome-encoded RNA helicases such as DDX3X and DDX3Y influence the formation of RNA granules in an ATP-independent manner but have different LLPS propensities (Shen H. et al, 2022). Nuclear import of granule-associated proteins is another important layer of SG regulation (Guo et al, 2018), and defects in nucleocytoplasmic transport are a significant pathogenic factor in ALS (Zhang et al, 2015;Gleixner et al, 2022). Cytoplasmic protein clumps, which are frequently observed in many neurodegenerative illnesses, impair nucleocytoplasmic transport, implying that abnormalities in nucleocytoplasmic transport might constitute a general cause of neurodegeneration (Hutten and Dormann, 2020;Gonzalez et al, 2021;Odeh et al, 2022).…”

The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD

“…We recently established a mouse model constitutively expressing an intermediate GR length, poly(GR)50, which develops mild behavioral and synaptic phenotypes (Verdone et al, 2022). While this model did not display TDP-43 mislocalization, it did show defects in the nuclear pore complex integrity, as revealed in aged mice by Nup62 mislocalization in the cytoplasm (Gleixner et al, 2022), suggesting that nuclear pore complex integrity does not univocally associate with neurodegeneration.…”