| NUP62 | |
|---|---|
| Full Name | Nucleoporin 62 |
| Chromosome | 19q13.33 |
| NCBI Gene ID | 23636 |
| Ensembl ID | ENSG00000213024 |
| OMIM ID | 605815 |
| UniProt ID | P37198 |
| Associated Diseases | [ALS](/diseases/als), [FTD](/diseases/ftd), [Huntington's Disease](/diseases/huntingtons-disease), Infantile Bilateral Striatal Necrosis |
NUP62 encodes nucleoporin 62 (also known as p62), a critical component of the nuclear pore complex (NPC) central channel. As a phenylalanine-glycine (FG)-repeat nucleoporin, NUP62 forms the selective permeability barrier that controls bidirectional macromolecular transport between the nucleus and cytoplasm. NUP62 is essential for neuronal function and survival, and its dysfunction has been directly implicated in multiple neurodegenerative diseases, most prominently in C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)[1].
The NUP62 protein contains an N-terminal FG-repeat domain that creates a hydrogel-like meshwork within the central channel of the NPC, functioning as a selective filter that allows passive diffusion of small molecules while requiring active, importin/exportin-mediated transport for larger cargo. Disruption of this barrier is increasingly recognized as a convergent pathological mechanism across multiple neurodegenerative diseases[2].
NUP62 is located on chromosome 19q13.33 and spans approximately 22 kb of genomic DNA. The gene encodes a 522-amino acid protein with a molecular weight of approximately 62 kDa. The protein consists of three functional domains:
NUP62 is highly expressed throughout the brain, with particularly high levels in the hippocampus, cortex, motor neurons, and Purkinje cells. Expression is maintained across the lifespan but nucleoporin turnover slows dramatically with aging — in post-mitotic neurons, NPC components including NUP62 can persist for decades, making them among the longest-lived proteins in the human body[3].
NUP62 is part of the NUP62-NUP58-NUP54 central channel subcomplex. This trimeric complex forms the constriction ring of the NPC and is essential for:
NUP62 mediates the transport of critical neuronal cargo:
In neurons, NUP62 plays specialized roles beyond general transport:
The most significant neurodegenerative disease connection for NUP62 involves C9orf72 repeat expansion-associated ALS and FTD. The GGGGCC hexanucleotide repeat expansion in C9orf72 produces toxic dipeptide repeat (DPR) proteins through repeat-associated non-ATG (RAN) translation. Two arginine-containing DPRs — poly(GR) and poly(PR) — directly disrupt NPC function by interacting with NUP62[4]:
Genetic modifier screens in Drosophila C9orf72 models have identified NUP62 as a potent suppressor of DPR toxicity — overexpression of NUP62 rescues neurodegeneration, confirming its centrality to disease pathogenesis[7].
NUP62 is disrupted in Huntington's disease through mutant huntingtin (mHTT) interactions:
Biallelic loss-of-function mutations in NUP62 cause infantile bilateral striatal necrosis, a devastating early-onset neurodegenerative disease characterized by:
Even in the absence of specific disease mutations, age-related deterioration of NUP62 contributes to neuronal vulnerability:
NUP62 biology has inspired several therapeutic strategies:
Chou CC et al. TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nature Neuroscience. 2018. ↩︎
Kim HJ, Taylor JP. Lost in transportation: nucleocytoplasmic transport defects in ALS and other neurodegenerative diseases. Neuron. 2017. ↩︎
Toyama BH et al. Identification of long-lived proteins reveals exceptional stability of essential cellular structures. Cell. 2013. ↩︎
Freibaum BD et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015. ↩︎ ↩︎
Shi KY et al. Toxic PRn poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export. Proceedings of the National Academy of Sciences. 2017. ↩︎
Gasset-Rosa F et al. Polyglutamine-expanded huntingtin exacerbates age-related disruption of nuclear integrity and nucleocytoplasmic transport. Neuron. 2017. ↩︎ ↩︎
Boeynaems S et al. Phase separation of C9orf72 dipeptide repeats perturbs stress granule dynamics. Molecular Cell. 2017. ↩︎
Grima JC et al. Mutant huntingtin disrupts the nuclear pore complex. Neuron. 2017. ↩︎ ↩︎
Basel-Vanagaite L et al. Mutated nup62 causes autosomal recessive infantile bilateral striatal necrosis. Annals of Neurology. 2006. ↩︎
D'Angelo MA et al. Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell. 2009. ↩︎ ↩︎