| NUP153 | |
|---|---|
| Full Name | Nucleoporin 153 |
| Chromosome | 6p22.3 |
| NCBI Gene ID | 9972 |
| Ensembl ID | ENSG00000124789 |
| OMIM ID | 603948 |
| UniProt ID | P49790 |
| Associated Diseases | [ALS](/diseases/als), [FTD](/diseases/ftd), [Alzheimer's Disease](/diseases/alzheimers-disease), [Huntington's Disease](/diseases/huntingtons-disease) |
NUP153 encodes nucleoporin 153, a critical component of the nuclear basket structure of the nuclear pore complex (NPC). As a dynamic phenylalanine-glycine (FG)-repeat nucleoporin positioned at the nuclear face of the NPC, NUP153 plays essential roles in nuclear import, mRNA export, chromatin organization, and DNA damage repair. NUP153 dysfunction is increasingly recognized as a convergent pathological feature of multiple neurodegenerative diseases, particularly in C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), where nuclear transport deficits represent a primary disease mechanism[1][2].
NUP153 serves as a key docking site for nuclear import receptors including importin-α/β and transportin-1, facilitating the translocation of transcription factors, RNA-binding proteins, and DNA repair enzymes into the nucleus. Its depletion leads to nuclear accumulation of RNA, cytoplasmic mislocalization of nuclear proteins, and impaired DNA damage responses—all hallmarks of neurodegenerative pathology[3].
NUP153 is located on chromosome 6p22.3 and spans approximately 65 kb. The gene encodes a 1,475-amino acid protein with a molecular weight of approximately 153 kDa. The protein contains three structurally and functionally distinct domains:
NUP153 is highly expressed in post-mitotic neurons, where NPCs are extraordinarily long-lived. Unlike dividing cells where NPC components are renewed during mitosis, neurons must maintain NUP153 through protein quality control mechanisms throughout their lifespan, making them especially vulnerable to age-related NUP153 dysfunction. Expression is particularly high in the hippocampus, cortex, and motor neurons[4].
NUP153 functions as a mobile nucleoporin that rapidly associates with and dissociates from the NPC (residence time ~seconds to minutes), in contrast to scaffold nucleoporins that remain stably associated for months. This dynamic behavior allows NUP153 to actively participate in transport:
NUP153 zinc finger domains directly bind chromatin at specific genomic loci, positioning superenhancers and developmentally regulated genes near the nuclear pore for efficient transcriptional activation and mRNA export. In neurons, NUP153-associated chromatin domains include genes required for synaptic plasticity and long-term potentiation, including BDNF, ARC, and FOS. Loss of NUP153-chromatin interactions leads to gene silencing and impaired activity-dependent transcription[5].
NUP153 is essential for the nucleocytoplasmic transport of DNA repair factors, particularly in the homologous recombination pathway. It facilitates nuclear import of BRCA1, 53BP1, and RAD51, and is required for mobilization of damaged DNA to the nuclear periphery where repair occurs in association with the NPC. In aging neurons, NUP153 decline contributes to accumulation of DNA damage and genomic instability[6].
The C9orf72 hexanucleotide repeat expansion (GGGGCC)ₙ, the most common genetic cause of ALS and FTD, directly impairs NUP153 function through multiple mechanisms:
Restoration of NUP153 levels rescues nuclear transport deficits and neuronal survival in C9orf72 iPSC-derived motor neuron models[2:1][7].
In AD, NUP153 protein levels decline with age and are further reduced in neurons bearing tau pathology. Hyperphosphorylated tau disrupts the nuclear lamina and NPC architecture, leading to NUP153 displacement from the nuclear envelope and accumulation of cytoplasmic NPC components. This results in:
Mutant huntingtin protein with expanded polyglutamine tracts physically disrupts NPCs and sequesters NUP153 in cytoplasmic aggregates. NUP153 is among the nucleoporins most depleted from the nuclear envelope in HD models, and its loss correlates with the severity of nuclear transport impairment in medium spiny neurons[8].
NUP153 is a critical node in age-related NPC deterioration. NPCs in post-mitotic neurons are among the longest-lived protein complexes in the body, with estimated half-lives exceeding years. NUP153, as a dynamic nucleoporin, is more susceptible to oxidative damage and turnover failure than scaffold components. Age-related loss of NUP153 has been directly linked to nuclear transport decline, accumulation of cytoplasmic TDP-43, and loss of nuclear envelope integrity in aging neurons[4:1].
NUP153 represents a compelling therapeutic target for restoring nuclear transport in neurodegeneration:
Fahrenkrog et al. The nuclear pore complex, nuclear transport, and apoptosis (2004). 2004. ↩︎
Zhang et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport (2015). 2015. ↩︎ ↩︎
Bastos et al. Targeting and function in mRNA export of nuclear pore complex protein Nup153 (1996). 1996. ↩︎
D'Angelo et al. Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells (2009). 2009. ↩︎ ↩︎
Ibarra et al. Nucleoporin-mediated regulation of cell identity genes (2016). 2016. ↩︎
Lemaitre et al. The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response (2012). 2012. ↩︎
Freibaum et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport (2015). 2015. ↩︎
Grima et al. Mutant Huntingtin disrupts the nuclear pore complex (2017). 2017. ↩︎