Table 1 |.
Summary of nucleoporin and nuclear transport receptor alterations in neurodegenerative disease models
| Proteins | Model system | Alterations | Biological impact | Refs |
|---|---|---|---|---|
| Amyotrophic lateral sclerosis | ||||
| NUP62 | FUS–ALS iPSN model | Altered nuclear rim staining pattern; possible cytoplasmic mislocalization | Unclear — might affect FUS phase separation | 11 |
| NUP98 | N2A cells that overexpress TDP43 C-terminal fragment | Probable reduction in levels in the nucleus | Unknown | 4 |
| NUP107 | Post-mortem motor cortex tissue from patients with C9orf72 ALS | Cytoplasmic mislocalization | Unknown | 10 |
| NUP205 | Fibroblasts that express mutant TDP43 | Probable reduction in levels in the nucleus | Unknown | 4 |
| NUP205 | Post-mortem frontal and motor cortex tissue from patients with C9orf72 ALS, TDP43 ALS and sporadic ALS | Cytoplasmic mislocalization | Unknown | 4,10 |
| POM121 | AAV GFP–(GR)200 mice | Subtle cytoplasmic mislocalization and/or co-accumulation with (GR)200; no obvious reduction in levels in the nucleus | Unclear in mice | 95 |
| POM121 | Primary spinal neurons that overexpress PFN1 variants | Cytoplasmic mislocalization | Unknown | 8 |
| POM121 | FUS–ALS iPSN model | Altered nuclear rim staining pattern | Unknown | 11 |
| RANGAP1 | Primary spinal neurons that overexpress PFN1 variants; fibroblasts that express mutant C9orf72; post-mortem motor cortex tissue from patients with C9orf72 ALS | Cytoplasmic mislocalization | Unclear — might contribute to deficient nucleocytoplasmic transport | 8,10 |
| RANGAP1 | Primary cortical neurons that overexpress TDP43 variants; C9orf72 ALS iPSN model; post-mortem motor cortex tissue from patients with C9orf72 ALS; AAV (G4C2)149 mice; AAV GFP–(PR)50 mice | Altered nuclear rim staining pattern | Unclear — might contribute to deficient nucleocytoplasmic transport | 4,10,92,94 |
| POM121 and RANGAP1 | AAV GFP–(GA)50 mice | Intranuclear co-accumulation with (GA)50; no obvious reduction in nuclear envelope staining | Unknown | 93 |
| NUP98, importin-α5, KPNA2 | AAV GFP–(GR)200 mice | Cytoplasmic mislocalization and/or co-aggregation with (GR)200 | Unclear — might contribute to deficient nucleocytoplasmic transport | 95 |
| POM121, NUP133, NUP50, NUP153, TPR | iPSN model of sporadic ALS | Reduction in levels in the NPC | Altered cellular distribution of RAN GTPase; impaired nucleocytoplasmic transport; TDP43 dysfunction and mislocalization | 97 |
| POM121, NDC1, GP210, NUP133, NUP107, NUP50, TPR, NUP98 | C9orf72 ALS iPSN model; post-mortem motor cortex and spinal cord tissue from patients with C9orf72 ALS | Reduction in levels in the NPC | Altered cellular distribution of RAN GTPase; impaired nucleocytoplasmic transport; TDP43 dysfunction and mislocalization | 5,97 |
| NUP50, NUP62, NUP93, NUP98, NUP107, NUP214, TPR, GLE1 | Primary cortical neurons that overexpress TDP43 variants | Cytoplasmic mislocalization and/or co-aggregation with TDP43 variants | Unknown | 4 |
| NUP35, NUP43, NUP58, NUP62, NUP88, NUP93, NUP98, NUP107, NUP153, NUP155, NUP160, NUP205, NUP214, NUP358, TPR, Aladin, hCG1, POM121, GP210, XPO5, NXF1, GLE1 | N2A cells that overexpress TDP43 C-terminal fragment | Cytoplasmic mislocalization and/or co-aggregation with TDP43 C-terminal fragment | Unknown | 4 |
| Alzheimer disease and frontotemporal dementia | ||||
| NUP62 | Post-mortem human hippocampal tissue | Perinuclear accumulation | Unknown | 6 |
| NUP98 | Tg4510 mice; post-mortem human hippocampal tissue; iPSNs that express mutant tau | Perinuclear accumulation, possibly within nuclear membrane invaginations | Contributes to altered RAN GTPase localization, which might affect nucleocytoplasmic transport; promotes tau aggregation | 6,123 |
| Huntington disease | ||||
| GLE1 | R6/2 mice; HTTQ175 mice | Intranuclear accumulation | Unknown — might reduce RNA export | 7 |
| NUP62 | R6/2 mice; post-mortem cortical and striatal human tissue; iPSN model of HD | Intranuclear accumulation; possible increase in expression; cytoplasmic mislocalization | Unknown | 9 |
| NUP88 | HTTQ175 mice | Intranuclear accumulation | Unknown | 9 |
| RANGAP1 | R6/2 mice; HTTQ175 mice; post-mortem cortical and striatal human tissue; human neuronal progenitor cells; iPSN model of HD | Intranuclear accumulation; possible increase in expression; abnormal nuclear distribution; abnormal nuclear membrane distribution; cytoplasmic mislocalization | Unknown | 7,9 |
AAV, adeno-associated virus; ALS, amyotrophic lateral sclerosis; FUS, fused in sarcoma; GA, glycine–alanine dipeptide repeat protein; GFP, green fluorescent protein; GP210, transmembrane nucleoporin; GR, glycine–arginine dipeptide repeat protein; HD, Huntington disease; Htt, huntingtin; iPSN, induced pluripotent stem cell-derived neuron; KPNA2, karyopherin-α 2; N2A, neuro2A; NDC1, transmembrane nucleoporin; NPC, nuclear pore complex; NXF1, nuclear RNA export factor 1; PFN1, profilin 1; POM121, transmembrane nucleoporin; RANGAP1, RAN GTPase-activating protein 1; TDP43, TAR DNA-binding protein 43; TPR, translocated promoter region nuclear basket nucleoporin; XPO5, exportin 5.