The Role of Nucleocytoplasmic Transport Defects in Amyotrophic Lateral Sclerosis
Abstract
:1. Introduction
2. Genetic Causes of ALS
2.1. Superoxide Dismutase 1
2.2. TAR DNA Binding Protein 43
2.3. Fused in Sarcoma
2.4. Chromosome 9 Open Reading Frame 72
3. ALS Histopathology
4. Nucleocytoplasmic Transport
4.1. The Nuclear Pore Complex (NPC)
4.1.1. Structure
4.1.2. Functions
4.2. Nuclear Transport Receptors (NTRs)
4.2.1. Introduction
4.2.2. Functions
4.3. The RanGTP Gradient
4.3.1. Introduction
4.3.2. Function
5. Evidence for Defective Nucleocytoplasmic Transport in ALS
5.1. Aberrant Subcellular Localization of Proteins
5.1.1. Mislocalization of Nucleocytoplasmic Transport Proteins
5.1.2. Mislocalization of Cargoes
5.2. Nucleocytoplasmic Transport Proteins as Modifiers of Disease
5.3. Functional Assays
6. Therapeutic Potential
7. Nucleocytoplasmic Transport and the Aging Brain
8. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Proteins | Observations | Models | Refs |
---|---|---|---|
Importins | |||
Importin-β1 | Irregular, disrupted at nuclear membrane, increased cytoplasmic localization | sALS, spinal cord | [84] |
Nuclear depletion | sALS, spinal cord | [85] | |
No abnormalities | mutant C9orf72 ALS | [87] | |
Importin-α1 | Nuclear depletion and cytoplasmic accumulation | mutant C9orf72 and sFTD | [88] |
Importin-α4 | Nuclear depletion and cytoplasmic accumulation | mutant C9orf72 and sFTD | [88] |
Nups—TM | |||
Gp210 | Abnormal nuclear precipitations and cytoplasmic upregulation | sALS, spinal cord | [86] |
Pom121 | Reduced expression (together with nup50, tpr, nup98, ndr1, nup107, nup133) | mutant C9orf72, motor cortex and spinal cord | [89] |
Nups—scaffolds | |||
Nup107 | Aggregates at nuclear membrane | mutant C9orf72 ALS, motor cortex | [83] |
Nup205 | Abnormal nuclear localization | mutant C9orf72 ALS, motor cortex | [83] |
Loss of immunoreactivity and large cytoplasmic inclusions | mutant TDP-43 + sALS, motor cortex | [90] | |
Abnormal perinuclear punctate staining | mutant C9orf72, motor cortex | [90] | |
No abnormalities | mutant SOD1, motor cortex | [90] | |
Nups—linkers | |||
Nup88 | Tortuous and redundant nuclear contours | mutant SOD1 ALS + sALS, spinal cord | [85] |
Nups—central channel | |||
Nup62 | Irregular disrupted nuclear membrane, aggregates, nuclear localization | sALS, spinal cord | [84] |
Tortuous and redundant nuclear contours | mutant SOD1 + sALS, spinal cord | [85] | |
Nup—outer structures | |||
Nup50 | Abnormal nuclear precipitations and cytoplasmic upregulation | sALS, spinal cord | [86] |
Ran gradient | |||
RanGap | Abnormal nuclear localization | mutant C9orf72 ALS, motor cortex | [83] |
Abnormal nuclear precipitations and cytoplasmic upregulation | SALS, spinal cord | [86] | |
No abnormalities | mutant TDP-43 + mutant C9orf72 + SALS motor cortex | [90] | |
No abnormalities | mutant C9orf72 ALS | [87] |
In Vitro | |||
Proteins | Observations | Models | Refs |
Importins | |||
TPNO3 | No abnormal staining | Patient-derived mutant C9orf72 induced neurons | [92] |
Importin-α3 | No abnormal staining | Patient-derived mutant C9orf72 induced neurons | [92] |
Exportins | |||
Exportin 5 | No abnormal staining | Patient-derived mutant C9orf72 induced neurons | [92] |
Nups | |||
Mab414 (nup62, nup153›, nup214, nup358) | Abnormal staining | Mutant TDP-43 iPSC motor neurons | [90] |
NPC proteins | Interaction with PR50 and GR50 | HEK293T cells expressing PR50 or GR50 | [41] |
Gle1, nup88, nup214, nup358, nup35, nup93, nup58, nup62, nup98, nup107, nup155, nup160 nup205, nup153, aladin, nxf1 | Aggregation together with TDP-43 CTF | BioID approach in Neuro-2a cells expressing TDP-43 CTF | [90] |
Nups—TM | |||
Pom121 | Mislocalization upon TDP-CTF OE | Neuro-2a cells cotransfected with plasmid expressing pom121 and TDP-43 CTF | [90] |
Reduced expression | Patient-derived mutant C9orf72 iPSC induced neurons | [89] | |
Gp210 | Mislocalization upon TDP-CTF OE | Neuro-2a cells cotransfected with plasmid expressing gp210 and TDP-43 CTF | [90] |
Nups—scaffolds | |||
Nup205 | Abnormal staining | Mutant TDP-43 and mutant C9orf72 patient fibroblasts | [90] |
No abnormal staining | Sporadic ALS patient fibroblasts | [90] | |
Nups—central channel | |||
Nup62 | Irregular nuclear contour | Spinal cord of SOD1G93A mouse model | [85] |
Nup98 | Disturbed distribution | Neuro-2a cells transfected with TDP-43 CTF | [90] |
Lamina | |||
Lamina B1 | Abnormal staining | Mutant TDP-43 and mutant C9orf72 patient fibroblasts | [90] |
No abnormal staining | Sporadic patient fibroblasts | [90] | |
Abnormal staining | Mutant TDP-43 iPSC motor neurons | [90] | |
Abnormal staining | Mouse primary cortical neurons expressing TDP-43 CTF/TDP-43Q331K/TDP-43M337V | [90] | |
No abnormal staining | Patient-derived mutant C9orf72 induced neurons | [92] | |
Ran gradient | |||
RanGAP | Nuclear puncta | S2 Drosophila cells transfected with (G4C2)30 | [83] |
Nuclear puncta | Mutant C9orf72 iPSC-derived neurons | [83] | |
Abnormal staining | Mouse primary cortical neurons expressing TDP 43 CTF or TDP-43-mtNLS | [90] | |
No abnormal staining | Mouse primary cortical neurons expressing TDP 43Q331K or TDP 43M337V | [90] | |
No abnormal staining | Patient-derived mutant C9orf72 induced neurons | [92] | |
RanGEF | Nuclear depletion | Patient derived mutant C9orf72 induced neurons | [92] |
Ran | Reduced nuclear/cytoplasmic ratio | S2 Drosophila cells transfected with (G4C2)30 | [83] |
Reduced nuclear/cytoplasmic ratio | Patient-derived mutant C9orf72 induced neurons | [83] | |
No change in nuclear/cytopIasmic ratio | Mouse primary cortical neurons expressing TDP-43 CTF or TDP-43-mtNLS | [90] | |
RAN export | |||
Thoc2 | Cytoplasmic mislocalization | HEK293T cells expressing TDP-43 fragments | [93] |
In vivo | |||
Proteins | Observations | Models | Refs |
Importins | |||
TPNO1 | Cytoplasmic aggregates | Prp-TDP-43A315T-GFP mouse model | [94] |
Importin-α1 | Cytoplasmic accumulation and nuclear depletion | Salivary gland cells of Drosophila expressing poly-GA64 or poly-GR64 | [88] |
Cytoplasmic accumulation and nuclear depletion | Salivary gland cells of Drosophila expressing ΔNLS-TDP-43, human TDP-43 or TDP-43Q331K | [88] | |
Cytoplasmic accumulation and nuclear depletion | Salivary gland cells of Drosophila expressing poly-GA64 or poly-GR64 | [88] | |
Importin-α4 | Cytoplasmic accumulation and nuclear depletion | Salivary gland cells of Drosophila expressing ΔNLS-TDP-43, human TDP-43 or TDP-43Q331K | [88] |
Nups | |||
Mab414 | No abnormal staining | Salivary gland cells of Drosophila expressing poly-GA64 or poly-GR64 | [88] |
(nup62, nup153, nup214, nup358) | No abnormal staining | Salivary gland cells of Drosophila expressing ΔNLS-TDP-43, human TDP-43 or TDP-43Q331K | [88] |
Nups—TM | |||
Gp210 | Increased nuclear localization | Spinal cord motor neurons of SOD1G93A mouse model | [86] |
Nups—Scaffolds | |||
Nup107 | Inclusions near nuclear envelope | Salivary gland cells of Drosophila expressing (G4C)58 | [35] |
Increased nuclear localization | Spinal cord motor neurons of SOD1G93A mouse model | [86] | |
Nup205 | Increased nuclear localization | Spinal cord motor neurons of SOD1G93A mouse model | [86] |
Nups—outer structures | |||
Nup50 | No abnormal staining | Salivary gland cells of Drosophila expressing poly-GA 64 or poly-GR64 | [88] |
Lamina | |||
Lamina C | Abnormal nuclear membrane | Salivary gland cells of Drosophila expressing (G4C2)58 | [35] |
Ran gradient | |||
RanGap | Increased nuclear localization | Spinal cord motor neurons of SOD1G93A mouse model | [86] |
No abnormal staining | Salivary gland cells of Drosophila expressing poly-GA64 or poly-GR64 | [88] | |
Increased nuclear localization | PrP-TDP43A315T GFP mouse model | [94] | |
Increased localization to nuclear invaginations | Mice expressing (G4C2)149 via intracerebroventricular injections with AAV | [95] |
Proteins | E/S | Observations | Models | Refs |
---|---|---|---|---|
Importins | ||||
Importin-β1 | 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] |
Assay | Models | Observations | Suggested Mechanism | Refs |
---|---|---|---|---|
Imp-β1/α1 | ||||
NLS-NES-GFP | Drosophila salivary glands expressing (G4C2)30 repeats | Reduced N/C ratio | RanGap sequestration in nuclear RNA foci | [107] |
Mutant C9orf72 iPSC-derived neurons | Reduced import based on FRAP | |||
GFP-NLS-NES | U2OS treated with PR20 peptides | Reduced import over time | Pores are blocked by poly-PR peptides | [45] |
BSA-NLS | Digitonin-treated HeLa cells exposed to PR20 peptides | Reduced import | ||
RFP-NLSTDP43 | HeLa cells transfected with GA149 expressing plasmid | Increased cytoplasmic levels | Cytoplasmic poly-GA aggregates | [100] |
HeLa cells transfected with GR149 expressing plasmid | No consistent differences observed | n.a. | ||
HeLa cells transfected with PR175 expressing plasmid | No differences observed | n.a. | ||
NES-tdTomato-NLS | Primary mouse cortical neurons expressing TDP-43 CTF/mTDP-43 | Reduced N/C ratio | TDP-43 aggregates sequester NC-transport proteins | [90] |
Fibroblasts of mutant C9orf72, TDP-43 and sALS patients | ||||
HEK293T cells transfected with PR50/GR50 expressing plasmids | Mislocalization of reporter | Stress granules sequester NC-transport proteins | [107] | |
ALS-FUS human spinal neurons and isogenic controls | Decreased nuclear import | Increased interaction of mutant FUS with Nup62 | [99] | |
Artificial importin-βcargo based on FRET | Permeabilized HeLa cells incubated with PR20 and GR20 peptides | Decreased nuclear import | Poly-PR and poly-GR bind and disrupt cargo loading of importin-β | [47] |
Fluorescent dextrans | Permeabilized HeLa cells incubated with PR20 and GR20 peptides | Increased passive transport | ||
Hormone-induced import assay: GCR2-GFP2-TDP43 or GCR2-GFP2-(MBP)-cNLS | HeLa cells incubated with TMR-GR25 peptides | Reduced import | Reduced solubility of importin-α/β via poly-GR binding | [46] |
HeLa cells incubated with TMR-PR25 peptides | No difference observed | n.a. | ||
NLSSV40-mNeonGreen2x-NESpki | HeLa cells incubated with GR20 or PR20 +/− leptomycin B (LMB) | No differences observed | n.a. | [108] |
HeLa cells transduced with GR100 or PR100 +/− LMB | No differences observed | n.a. | ||
SH-SY5Y cells transduced with GR100 or PR100 +/− LMB | No differences observed | n.a. | ||
iPSC-derived MNs transduced with GR100 or PR100 +/− LMB | No differences observed | n.a. | ||
NLSc-myc-GFP2x-NESikb2 | HeLa cells transduced with GR100 or PR100 | No differences observed | n.a. | |
TPNO | ||||
RFP-NLSpY(hnRNPA1) | HeLa cells transfected with GA149, GR149 or PR175 expressing plasmids | No differences observed | n.a. | [100] |
YFP-M9-CFP | Digitonin treated HeLa cells incubated with PR20 and GR20 peptides | Decreased nuclear import | Poly-PR and poly-GR bind and disrupt cargo loading of TPNO1 | [47] |
NESpki-mNeonGreen2x-NLSFUS | HeLa cells incubated with GR20 or PR20 | No differences observed | n.a. | [108] |
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Vanneste, J.; Van Den Bosch, L. The Role of Nucleocytoplasmic Transport Defects in Amyotrophic Lateral Sclerosis. Int. J. Mol. Sci. 2021, 22, 12175. https://doi.org/10.3390/ijms222212175
Vanneste J, Van Den Bosch L. The Role of Nucleocytoplasmic Transport Defects in Amyotrophic Lateral Sclerosis. International Journal of Molecular Sciences. 2021; 22(22):12175. https://doi.org/10.3390/ijms222212175
Chicago/Turabian StyleVanneste, Joni, and Ludo Van Den Bosch. 2021. "The Role of Nucleocytoplasmic Transport Defects in Amyotrophic Lateral Sclerosis" International Journal of Molecular Sciences 22, no. 22: 12175. https://doi.org/10.3390/ijms222212175