Table 2 Summary of NTR and nucleoporin defects in ALS/FTLD-TDP brain and spinal cord autopsy tissue
From: Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD
Protein | Tissue | Reported defects | Clinical cases | Analysis type |
|---|---|---|---|---|
α-importins | ||||
 KPNA2 | FTLD-TDP temporal cortex | Decreased nuclear and cytoplasmic labelling due to reduced protein levels [212] | 11 FTLD-TDP (3F, 8 M), 9 controls (5F, 4 M) | Qualitative and blinded semi-quantitative |
sALS spinal cord | Enhanced cytoplasmic staining due to increased protein levels [212] | 10 sALS (6F, 4Â M), 10 controls (3F, 7Â M) | Qualitative and blinded semi-quantitative | |
 KPNA4 | C9ALS/FTLD and sFTLD-TDP frontal cortex | Decreased nuclear labelling, colocalization with pTDP-43 inclusions, weak colocalization with poly-GA, GP, and GR inclusions [240] | 8 C9ALS/FTLD, sporadic FTLD-TDP, 8 controls | Blinded qualitative |
 KPNA6 | sALS spinal cord | Decreased protein levels [212] | 10 sALS (6F, 4 M), 10 controls (3F, 7 M) | Qualitative and blinded semi-quantitative |
β-importins | ||||
 KPNB1 | sALS spinal cord | Decreased nuclear and increased cytoplasmic reactivity of KPNB1 [243] | 7 sALS (3F, 4 M), 6 controls (3F, 3 M) | Qualitative |
ALS spinal cord AHCs | Decreased nuclear labelling and cytoplasmic accumulation [244] | 6 ALS (3F, 3Â M), 6 controls (5Â M, 1F) | Quantitative | |
C9ALS spinal cord | Depletion from the nucleus and nuclear envelope and cytoplasmic accumulation [245] | 11 C9ALS cases (4F, 7Â M), 8 non-C9ALS (4F, 4Â M), 3 controls (1F, 2Â M, 2AD/DLB), | Qualitative | |
sALS spinal cord | Depletion from the nucleus or irregular nuclear KPNB1 staining in cells with TDP-43-positive inclusions [246] | Number of cases or controls unclear | Qualitative | |
sALS spinal cord | Disrupted nuclear staining and increased cytoplasmic KPNB1 expression in cells with TDP-43 inclusions [247] | 6 sALS (5Â M, 1F), 7 controls (6Â M, 1F) | Qualitative and quantitative | |
sALS, TDP-ALS, C9ALS, sFTLD-TDP, c9FTLD-TDP hippocampus, motor cortex and spinal cord | Loss from the nucleus and sequestration into pTDP-43 inclusions [42] | 2 C9ALS (1F, 1Â M), 2 sALS (1F, 1Â M), 2 SOD1-ALS (1F, 1Â M), 1 FUS-ALS (1F, 0Â M), 1 FUS-ALS (0F, 1Â M), 1 TARDP-ALS (0F, 1Â M), 2 C9FTLD-A (1F, 1Â M), 2 C9FTLD-B (0F, 2Â M), 4 controls (0F, 4Â M) | Qualitative | |
 TNPO1 | FTLD-FUS frontal cortex, hippocampus, medulla, and spinal cord | Nuclear and cytoplasmic aggregation, colocalization with FUS inclusions [248] | 6 NIFID (5F, 1 M), 7 aFTLD-U (3F, 4 M), 3 MSA, 3 CBD, 3 MND, 3 AD, 3 PD, 3 PSP, 3 PiD, 1 FTLD-TDP-1, 3 FTLD-TDP-2, 1 FTLD-TDP-3, 3 controls | Qualitative |
FTLD-FUS hippocampus and cerebral white matter | Nuclear and cytoplasmic aggregation [249] | 17 aFTLD-U (9F, 8Â M), 8 BIBD (3F, 5Â M), 4 NIFID (3F, 1Â M), 6 ALS-FUS (4F, 2Â M), 6 FTLD-TDP (2 Type A, 2 Type B, 2 Type C), 9 FTLD-Tau (2 PiD, 2 CBD, 5 PSP), 2 CHMP2B-FTLD, 3 FTLD-ni, 2 sALS-TDP, 2 SOD1-ALS, 2 AD, 4 DLB, 8 PD, 2 MSA, 2 HD, 3 SCA (1 SCA-1, 2 SCA-3), 1 NIBD, 4 controls | Qualitative | |
FTLD-FUS hippocampus and temporal cortex | Cytoplasmic aggregation [250] | 5 aFTLD-U (1F, 4Â M), 2 NIFID (2F, 0Â M), 1 BIBD (0F, 1Â M) | Qualitative and semi-quantitative | |
FTLD-FUS frontal cortex | Cytoplasmic aggregation, colocalization with FUS inclusions [251] | 3 FUS-ALS (2F, 1Â M), 3 C9-ALS (0F, 3Â M), 7 sALS (5Â M, 2F), 3 FTLD- FUS (3F, 0Â M), 6 FTLD-TDP (3F, 3Â M), 1 AD, 7 controls | Qualitative | |
Exportins | ||||
 XPO2 | FTLD-TDP temporal cortex | Decreased nuclear and cytoplasmic labelling due to reduced protein levels [212] | 11 FTLD-TDP (3F, 8 M), 9 controls (5F, 4 M) | Qualitative and blinded semi-quantitative |
Nucleoporins | ||||
 NUP50 | sALS lumbar spinal cord | Nuclear aggregation [252] | 3 ALS, 1 control | Qualitative |
 NUP54 | sALS spinal cord | Colocalization with pTDP-43 inclusions [253] | 2 C9ALS/FTLD (1F, 1 M), 2 sALS (1F, 1 M), 1 sALS/FTLD (0F, 1 M), 2 FTLD-FUS (0F, 2 M), 1 control (0F, 1 M) | Qualitative and semi-quantitative |
 NUP62 | sALS and SOD1-ALS spinal cord | Irregular nuclear contour staining [243] | 7 sALS (3F, 4 M), 4 SOD1-fALS (0F, 4 M), 6 controls (3F, 3 M) | Semi-quantitative |
ALS spinal cord AHCs | Depletion from the nuclear envelope [244] | 6 ALS (3F, 3Â M), 6 controls (5Â M, 1F) | Quantitative | |
sALS spinal cord AHCs | Nuclear depletion in ADAR2- and TDP-43-negative cells, disrupted nuclear staining in cells with cytoplasmic TDP-43 inclusions [246] | No indication of number of cases or controls | Qualitative | |
sALS spinal cord | Depletion or disruption of Nup62 staining in cells with mislocalized TDP-43 [247] | 6 sALS (5Â M, 1F), 7 controls(6Â M, 1F) | Qualitative and quantitative | |
sALS medial temporal cortex and spinal cord; C9ALS/FTLD hippocampus and spinal cord | Nuclear disruption, colocalization with pTDP-43 inclusions [253] | 2 C9ALS/FTLD (1F, 1Â M), 2 sALS (1F, 1Â M), 1 sALS/FTLD (0F, 1Â M), 2 FTLD-FUS (0F, 2Â M), 1 control (0F, 1Â M) | Qualitative and semi-quantitative | |
sALS, TDP-ALS, C9ALS, sFTLD-TDP, c9FTLD-TDP hippocampus, motor cortex and spinal cord | Loss from the nuclear envelope and sequestration into pTDP-43 inclusions [42] | 2 C9ALS (1F, 1Â M), 2 sALS (1F, 1Â M), 2 SOD1-ALS (1F, 1Â M), 1 FUS-ALS (1F, 0Â M), 1 FUS-ALS (0F, 1Â M), 1 TARDP-ALS (0F, 1Â M), 2 C9FTLD-A (1F, 1Â M), 2 C9FTLD-B (0F, 2Â M), 4 controls (0F, 4Â M) | Qualitative | |
 NUP88 | sALS and SOD1-ALS lumbar spinal cord | Irregular nuclear contour staining [243] | 7 sALS (3F, 4 M), 6 controls (3F, 3 M) | Qualitative |
 NUP98 | C9ALS/FTLD hippocampus and medial temporal cortex | Colocalization with p62 inclusions [253] | 2 C9ALS/FTLD (1F, 1 M), 2 sALS (1F, 1 M), 1 sALS/FTLD (0F, 1 M), 2 FTLD-FUS (0F, 2 M), 1 control (0F, 1 M) | Qualitative and semi-quantitative |
 NUP107 | C9ALS motor cortex | Abnormal perinuclear aggregation [232] | 6 C9ALS (4F, 2 M), 5 non-C9ALS (3F, 2 M), 2 C9ALS/FTLD (0F, 2 M), 6 controls (3F, 3 M) | Qualitative and semi-quantitative |
 NUP153 | sALS and SOD1-ALS lumbar spinal cord | Irregular nuclear contour staining [243] | 7 sALS (3F, 4 M), 6 controls (3F, 3 M) | Qualitative |
 NUP205 | C9ALS motor cortex | Abnormal nuclear staining [232] | 6 C9ALS (4F, 2 M), 5 non-C9ALS (3F, 2 M), 2 C9ALS/FTLD (0F, 2 M), 6 controls (3F, 3 M) | Qualitative and semi-quantitative |
sALS lumbar spinal cord | Colocalization with TDP-43 inclusions [252] | 3 ALS, 1 control | Qualitative | |
sALS and TDP-ALS motor cortex; C9ALS motor cortex; sALS, TDP-ALS and C9ALS frontal cortex; TDP-ALS motor cortex and hippocampus | Loss of nuclear envelope immunoreactivity, formation of large cytoplasmic inclusions, and colocalization with pTDP-43 aggregates [216] | 2 TARDP-ALS (0F, 2Â M), 7 C9ALS (4F, 3Â M), 1 SOD1-ALS (1F, 0Â M), 15 sALS (6F, 9Â M), 10 controls (4F, 6Â M) | Qualitative | |
 GP210 | sALS lumbar spinal cord | Increased staining in nuclear envelope and cytoplasm [252] | 3 ALS, 1 control | Qualitative |