| Protein | Nucleoporin 62 (NUP62, p62) |
|---|---|
| Encoded by | [NUP62](/genes/nup62) |
| UniProt | [P37198](https://www.uniprot.org/uniprot/P37198) |
| Molecular weight | ~53 kDa |
| Subcellular localization | Nuclear pore complex (central channel) |
| Protein family | FG-nucleoporin family |
| Key disease links | [ALS](/diseases/als), [FTD](/diseases/ftd), [Alzheimer's disease](/diseases/alzheimers-disease) |
NUP62 (Nucleoporin 62, p62) is a critical component of the nuclear pore complex (NPC) central transport channel, where it forms the NUP62 sub-complex together with NUP54 and NUP58.[1][2] Through its phenylalanine-glycine (FG) repeat domain, NUP62 creates a selective permeability barrier that governs nucleocytoplasmic transport of proteins and RNA — a process increasingly recognized as fundamentally disrupted in neurodegenerative diseases including ALS, FTD, and Alzheimer's disease.[3][4]
NUP62 contains an N-terminal FG-repeat domain (~200 residues) that is intrinsically disordered and forms the hydrogel-like meshwork within the NPC central channel.[1:1][5] The C-terminal coiled-coil domain mediates trimerization with NUP54 and NUP58 to anchor the complex within the NPC scaffold.[2:1] O-linked N-acetylglucosamine (O-GlcNAc) modification of the FG-repeat domain dynamically regulates pore permeability and transport selectivity.[6] The FG-repeat domain can undergo liquid-liquid phase separation (LLPS), forming hydrogel-like condensates that recapitulate the NPC selectivity barrier in vitro.[5:1]
In healthy neurons, NUP62 performs several essential functions:
Nucleocytoplasmic transport dysfunction mediated by NUP62 degradation is emerging as a convergent pathomechanism across multiple neurodegenerative diseases:
C9orf72 hexanucleotide repeat expansions — the most common genetic cause of ALS/FTD — produce dipeptide repeat proteins (DPRs) that directly bind and disrupt NUP62 FG-repeat hydrogels, collapsing the NPC selectivity barrier.[4:1][10] Poly-glycine-alanine (poly-GA) and poly-proline-arginine (poly-PR) DPRs show particular affinity for NUP62, displacing transport receptors and causing cytoplasmic mislocalization of nuclear proteins including TDP-43.[11] TDP-43 mislocalization itself further damages NPCs by sequestering NUP62 mRNA, creating a self-amplifying destructive cycle.[12]
Tau pathology disrupts NPC integrity through direct interaction with NUP62. Hyperphosphorylated tau binds the NUP62 FG domain, impairing nuclear import of transcription factors essential for neuronal survival.[13] In human AD brain tissue, NUP62 levels are reduced by 30-50% in neurons bearing neurofibrillary tangles, correlating with impaired Ran-GTPase gradient maintenance.[14] Amyloid-beta oligomers also indirectly deplete NUP62 through oxidative modification of the O-GlcNAc cycling machinery.[6:1]
Age-dependent oxidative damage to long-lived NUP62 protein (NPC components are among the most stable proteins in neurons, with half-lives exceeding years) progressively degrades transport fidelity, potentially establishing a vulnerability threshold for neurodegeneration.[15][16]
Strategies to restore NUP62 function and nucleocytoplasmic transport integrity include:
Chug H, Trakhanov S, Hülsmann BB, et al. Crystal structure of the metazoan Nup62-Nup58-Nup54 nucleoporin complex. Science. 2015. ↩︎ ↩︎ ↩︎
Grandi P, Dang T, Pané N, et al. Nup93 is a component of the nuclear pore complex connecting the inner basket with the central channel. J Cell Biol. 1997. ↩︎ ↩︎
Kim HJ, Taylor JP. Lost in transportation: nucleocytoplasmic transport deficits in ALS and other neurodegenerative diseases. Neuron. 2017. ↩︎ ↩︎
Freibaum BD, Lu Y, Lopez-Gonzalez R, et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015. ↩︎ ↩︎
Schmidt HB, Görlich D. Nup98 FG domains from diverse species spontaneously phase-separate into particles with nuclear pore-like permselectivity. eLife. 2015. ↩︎ ↩︎
Zhu Y, Liu TW, Madden Z, et al. Post-translational O-GlcNAcylation is essential for nuclear pore integrity and maintenance of the pore selectivity filter. J Biol Chem. 2016. ↩︎ ↩︎ ↩︎
Wickramasinghe VO, McMurtrie PI, Mills AD, et al. mRNA export from mammalian cell nuclei is dependent on GANP. Curr Biol. 2010. ↩︎
Ibarra A, Benner C, Tyber A, Hetzer MW. Nucleoporin-mediated regulation of cell identity genes. Genes Dev. 2016. ↩︎
Lemaitre C, Fischer B, Kalousi A, et al. The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response. Oncogene. 2011. ↩︎
Shi KY, Mack E, Bhatt DL, et al. Toxic PRn poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export. Proc Natl Acad Sci USA. 2017. ↩︎ ↩︎
Zhang K, Donnelly CJ, Haeusler AR, et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015. ↩︎ ↩︎
Chou CC, Zhang Y, Bhatt DL, et al. TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nat Neurosci. 2018. ↩︎
Eftekharzadeh B, Daiber JA, Bhatt DL, et al. Tau protein disrupts nucleocytoplasmic transport in Alzheimer's disease. Neuron. 2018. ↩︎
Sheffield LG, Miskiewicz HB, Tannenbaum LB, Bhatt DL. Nuclear pore complex proteins in Alzheimer disease. J Neuroimmune Pharmacol. 2006. ↩︎
D'Angelo MA, Raices M, Bhatt DL, et al. Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell. 2009. ↩︎
Toyama BH, Savas JN, Park SK, et al. Identification of long-lived proteins reveals exceptional stability of histones and nuclear pore complexes. Cell. 2013. ↩︎
Haines JD, Herbin O, de la Hera B, et al. Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination. Nat Neurosci. 2015. ↩︎