Atypical nuclear envelope condensates linked to neurological disorders reveal nucleoporin-directed chaperone activities

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

“…Consistent with our findings, essential functions have not been identified for Nup foci observed in cell culture, including GLFG bodies and CyPNs (cytoplasmic accumulations of PML and nucleoporins)(Jul-Larsen et al , 2009; Griffis et al , 2002). In contrast, several studies suggest connections to stress and disease, including 1) Nup accumulation in stress granules (Zhang et al , 2018; Agote-Aran et al , 2020), 2) aberrant condensation of Nup98 and Nup214 fusion proteins driving oncogenic transformation in certain leukemias (Zhou & Yang, 2014; Chandra et al , 2022; Terlecki-Zaniewicz et al , 2021), 3) the formation of nuclear envelope associated Nup condensates in models of DYT1 dystonia (Prophet et al , 2022), and 4) the presence of Nups in pathological inclusions in primary patient samples and models of neurodegenerative disease (Chandra & Lusk, 2022; Fallini et al , 2020; Hutten & Dormann, 2020). We find that overexpression of Nup98 in neurons initiates the formation of toxic condensates that cause neuronal dysfunction.…”

Nuclear Pore Complex Dysfunction in Dystonia Pathogenesis: Nucleoporins in the Spotlight

“…First, the authors highlight the formation of abnormal "bleb"-like herniations containing nonfunctional FG-NUPs at the nuclear envelope of affected cells, resulting in NPC-biogenesis deficits. 2,3 Second, they demonstrate that FG-NUP-enriched condensates in "blebs" result in sequestration of protein quality-control network components such as HSP40/HSP70 chaperones, triggering a cascade of proteotoxic stress. 2 Both pathological effects observed in relation to mutant torsinA implicate FG-NUP perturbation in the genesis of early-onset dystonic movements, most likely via mechanisms of impaired nucleocytoplasmic shuttling, compromised intracellular proteostasis, or a combination thereof.…”

“…Dysfunction of torsinA induced by a recurrent mutation in TOR1A has been identified as the first monogenic cause of dystonia, 1 but the pathogenesis of clinical manifestations is still incompletely understood. In an article published in the Nature series, Prophet and colleagues 2 now provide fascinating insights into the roles of nuclear pore complexes (NPCs) and a subset of its components, the phenylalanine‐glycine‐rich region‐containing nucleoporins (FG‐NUPs), in the etiology of TOR1A ‐related dystonia. NPCs are cylindrical channels in the nuclear envelope, controlling bidirectional exchange of biomolecules, and built from about 30 different nucleoporins 3 .…”

“…The highly conserved group of FG‐NUPs (NUP98, NUP54, NUP62, and others) line the interior of NPCs, forming a permeability barrier, and thus represent key mediators of nucleocytoplasmic transport 3 . By studying virally derived model proteins tied to nuclear transport, comparative mass spectrometry–based proteomics data, and microscopic ultrastructural changes in torsinA knock‐out cell lines and primary mouse neurons, Prophet and colleagues 2 reveal two main mechanisms contributing to cellular pathology in the context of torsinA dysfunction. First, the authors highlight the formation of abnormal “bleb”‐like herniations containing nonfunctional FG‐NUPs at the nuclear envelope of affected cells, resulting in NPC‐biogenesis deficits 2,3 .…”

“…By studying virally derived model proteins tied to nuclear transport, comparative mass spectrometry–based proteomics data, and microscopic ultrastructural changes in torsinA knock‐out cell lines and primary mouse neurons, Prophet and colleagues 2 reveal two main mechanisms contributing to cellular pathology in the context of torsinA dysfunction. First, the authors highlight the formation of abnormal “bleb”‐like herniations containing nonfunctional FG‐NUPs at the nuclear envelope of affected cells, resulting in NPC‐biogenesis deficits 2,3 . Second, they demonstrate that FG‐NUP‐enriched condensates in “blebs” result in sequestration of protein quality‐control network components such as HSP40/HSP70 chaperones, triggering a cascade of proteotoxic stress 2 .…”