Skip to main content
. 2021 Nov 10;22(22):12175. doi: 10.3390/ijms222212175

Table 3.

Modifiers of toxicity. Summary of all the ALS-related models in which the effect of changing nucleocytoplasmic transport proteins on the different phenotypes was determined. S indicates suppressors. A protein is defined as a suppressor when a loss of function (LOF) suppresses the phenotype, a gain of function (GOF) enhances the phenotype or overexpression (OE) enhances the phenotype. E indicates an enhancer. A protein is defined as an enhancer when a LOF enhances the phenotype, a GOF suppresses the phenotype or OE suppresses the phenotype.

Proteins E/S Observations Models Refs
Importins
Importin- β 1 E LOF enhances phenotype Drosophila expressing poly-GR50 [41]
E LOF enhances phenotype Drosophila expressing poly-PR25 [37]
Importin-α1 S OE enhances phenotype Drosophila (G4C2)30—no DPRs detected [83]
S LOF suppresses phenotype Drosophila expressing poly-GR50 [41]
Importin-α3 E OE suppresses phenotype Yeast expressing poly-PR50 [92]
E LOF enhances phenotype Drosophila expressing poly-PR25 [37]
E OE suppresses NC-transport phenotype HeLa cells expressing GA149 [100]
Importin-α4 E LOF enhances phenotype Drosophila expressing poly-GR50 [41]
E LOF enhances phenotype Drosophila expressing poly-PR25 [37]
E OE suppresses NC-transport phenotype HeLa cells expressing GA149 [100]
TPNO1 E LOF enhances phenotype Drosophila (G4C2)58—DPRs detected [35]
E OE suppresses phenotype Yeast expressing poly-PR50 [92]
E LOF enhances phenotype Drosophila expressing poly-GR50 [41]
E LOF enhances phenotype Drosophila expressing poly-PR25 [37]
TPNO3 E OE suppresses phenotype Yeast expressing poly-PR50 [92]
Importin 4 S LOF suppresses phenotype Drosophila expressing poly-PR25 [37]
Importin 5 S LOF suppresses phenotype Drosophila expressing poly-GR50 [41]
Importin 7 S LOF suppresses phenotype Drosophila expressing poly-GR50 [41]
Importin 9 E OE suppresses phenotype Yeast expressing poly-PR50 [92]
Importin 11 E OE suppresses phenotype Yeast expressing poly-PR50 [92]
E LOF enhances phenotype Drosophila expressing poly-PR25 [37]
Exportins
Exportin 1 S LOF suppresses phenotype–confirmed by KPT-276 Drosophila (G4C2)30—no DPRs detected [83]
S LOF suppresses phenotype Drosophila expressing human FUSR521G [101]
E LOF enhances phenotype—confirmed by LMB Drosophila (G4C2)58 - DPRs detected [35]
E LOF enhances phenotype Drosophila expressing poly-GR50 [41]
E LOF enhances phenotype Drosophila expressing poly-PR25 [37]
S 2.5 nM KPT-350/KPT-335 is mildly protective (no impaired transport) Rat cortical neurons OE human TDP-43WT [102]
E 10 nM KPT-350/KPT-335 is toxic Rat cortical neurons OE human TDP-43WT [102]
KPT-350 induces a partial rescue limited by weight loss Rat model AAV9 brain injected TDP-43 mRNA [102]
S KPT-335 treatment suppresses phenotype Mouse cortical neurons expressing TDP-43 CTF or TDP-43Q331K [90]
S 1 µM KPT-335/KPT-276 treatment suppresses phenotype Drosophila TDP-43WT or TDP-43Q331K OE [90]
E 150 nM KPT335/KPT-276 treatment enhances phenotype Mouse cortical neurons expressing TDP-43 CTF or TDP-43Q331K [90]
E 5 µM KPT-335/KPT-276 Drosophila TDP-43WT or TDP-43Q331K OE [90]
Exportin 5 E OE suppresses phenotype Yeast expressing poly-PR50 [92]
Nups—TM
Ndc1 S OE enhances phenotype Yeast expressing poly-PR50 [92]
Nups—scaffolds
Nup107 S LOF suppresses phenotype Drosophila (G4C2)58 - DPRs detected [35]
S LOF suppresses phenotype Drosophila TDP-43WT or TDP-43Q331K OE [90]
S LOF suppresses phenotype Drosophila expressing poly-PR25 [37]
Nup160 S LOF suppresses phenotype Drosophila (G4C2)58 - DPRs detected [35]
Nup205 S LOF suppresses phenotype Drosophila expressing poly-GR50 [41]
Seh1 E LOF enhances phenotype Drosophila expressing poly-PR25 [37]
Nup155 S LOF suppresses phenotype Drosophila expressing poly-PR25 [37]
S LOF suppresses phenotype Drosophila expressing human FUSR521G [101]
Nups—linkers
Nup93 S LOF suppresses phenotype Drosophila TDP-43WT or TDP-43Q331K OE [90]
E LOF enhances phenotype Drosophila expressing poly-PR25 [37]
Nups—central channel
Nup96—Nup98 S LOF suppresses phenotype Drosophila (G4C2)58 - DPRs detected [35]
S LOF suppresses phenotype Drosophila TDP-43WT or TDP-43Q331K OE [90]
S LOF suppresses phenotype Drosophila FUSWT, FUSR518K, FUSR521C OE [99]
Nup62 E LOF enhances phenotype Drosophila expressing poly-PR25 [37]
S LOF suppresses phenotype Drosophila FUSWT, FUSR518K, FUSR521C OE [99]
S OE enhances phenotype Drosophila FUSWT, FUSR518K, FUSR521C OE [99]
E OE suppresses NC-transport phenotype HeLa cells expressing GA149 [100]
Nup54 E OE suppresses NC-transport phenotype HeLa cells expressing GA149 [100]
S LOF suppresses phenotype Drosophila FUSWT, FUSR518K, FUSR521C OE [99]
Nups—outer structures
Nup50 E LOF enhances phenotype Drosophila (G4C2)58 - DPRs detected [35]
S LOF suppresses phenotype Drosophila expressing poly-PR25 [37]
Nup153 E LOF enhances phenotype Drosophila (G4C2)58—DPRs detected [35]
Nup214 S LOF suppresses phenotype Drosophila TDP-43WT or TDP-43Q331K OE [90]
S LOF suppresses phenotype Drosophila FUSWT, FUSR518K, FUSR521C OE [99]
Tpr E LOF enhances phenotype Drosophila expressing poly-PR25 [37]
RanGradient
RanGap E GOF mutation/OE suppresses phenotype Drosophila (G4C2)30—no DPRs detected [83]
E LOF enhances phenotype Drosophila expressing poly-PR25 [37]
RanGEF S OE enhances phenotype Drosophila (G4C2)30—no DPRs detected [83]
S OE enhances phenotype Yeast expressing poly-PR50 [92]
E LOF enhances phenotype Drosophila expressing poly-PR25 [37]
Ran E Dominant negative mutation enhances phenotype Drosophila (G4C2)58—DPRs detected [35]
RAN export
Alyref S LOF suppresses phenotype Drosophila (G4C2)58—DPRs detected [35]
Gle1 E LOF enhances phenotype Drosophila (G4C2)58—DPRs detected [35]