Table 1 Genetic models exploring association of TDP-43 with NMJ pathology
From: TDP-43 dysregulation and neuromuscular junction disruption in amyotrophic lateral sclerosis
Animal model/study | TDP-43 expression | Observed phenotypes | ||||||
|---|---|---|---|---|---|---|---|---|
NMJ defects | Impaired synaptic transmission at the NMJa | Axonopathy | Muscle pathology | Motor deficits | Decreased lifespan | MN loss | ||
Fruit fly (Drosophila melanogaster) | ||||||||
TBPH KO (chromosomal deletion) | ✓ | na | na | X | ✓ | ✓ | X | |
Li et al. [38] | hTDP-43 OE in MNs | ✓ | na | ✓ | na | ✓ | ✓ | ✓ |
Lin et al. [43] | TBPH KO (imprecise excision) | ✓ | na | ✓ | na | ✓ | ✓ | na |
TBPH OE in MNs | ✓ | na | ✓ | na | ✓ | ✓ | na | |
TBPH KD in neurons | ✓ | na | na | na | ✓ | na | na | |
Wang et al. [40] | TBPH KO (chromosomal deletion) | X | na | na | na | ✓ | ✓ | na |
TBPH OE in MNs | ✓ | na | na | na | na | na | na | |
hTDP-43 OE in MNs | ✓ | na | na | na | na | na | na | |
hTDP-43 M337V OE in MNs | X | na | na | na | na | na | na | |
Diaper et al. [44] | TBPH KO (imprecise excision) | X | ✓ | na | X | ✓ | ✓ | ✓ |
TBPH OE (single inserts) | X | ✓ | na | na | ✓ | ✓ | ✓ | |
TBPH KD in neurons (RNAi) | na | ✓ | na | na | ✓ | na | na | |
TBPH KD in muscle (RNAi) | na | X | na | na | na | na | na | |
TBPH KD in upper MNs (RNAi) | na | ✓ | ✓ | na | ✓ | X | ✓ | |
TBPH OE in upper MNs | na | ✓ | ✓ | na | ✓ | X | ✓ | |
Estes et al. [42] | hTDP-43 WT OE in MNs | ✓ | na | ✓ | na | ✓ | ✓ | ✓ |
hTDP-43 A315T OE in MNs | X | na | X | na | ✓ | ✓ | ✓ | |
hTDP-43 A315T OE (high expression) in MNs | ✓ | na | X | na | ✓ | ✓ | ✓ | |
Estes et al. [45] | hTDP-43 WT, D169G, G298S, A315T, N345K OE in neurons | ✓ | na | na | na | ✓ | na | na |
hTDP-43 WT, D169G, G298S, A315T, N345K OE in glia (pan-glial) | ✓ | na | na | na | ✓ | na | na | |
hTDP-43 WT, G298S OE in MNs | ✓ | ✓ | na | na | ✓ | ✓ | na | |
Romano et al. [46] | Inducible KD of TBPH in neurons (RNAi) | ✓ | na | na | na | ✓ | ✓ | na |
Inducible OE of TBPH in neurons | na | na | na | na | ✓ | na | na | |
Deshpande et al. [47] | TBPH KO (chromosomal deletion) | ✓ | na | na | na | na | ✓ | na |
hTDP-43 OE in MNs | ✓ | na | na | na | na | ✓ | na | |
Strah et al. [104] | TBPH KO (chromosomal deletion) | ✓ | ✓ | ✓ | na | ✓ | na | na |
TBPH KD in muscle (RNAi) | ✓ | na | na | X | ✓ | ✓ | na | |
Lee et al. [254] | hTDP-43 OE in glia (pan-glial) | ✓ | na | na | na | ✓ | ✓ | na |
Zebrafish (Danio rerio) | ||||||||
hTDP-43 A315T, G348C, A382T OE | na | na | ✓ | na | ✓ | na | ✓ | |
tardbp KD (AMO) | ✓ | na | ✓ | na | ✓ | na | X | |
hTDP-43 G348C OE | ✓ | ✓ | na | X | ✓ | na | ✓ | |
Dzieciolowska et al. [50] | tardbpl KD (AMO) | ✓ | X | na | na | X | X | na |
tardbp Y220X (unstable and degraded tdp-43) | ✓ | X | na | na | X | X | na | |
tardbp Y220X + tardbpl KD | ✓ | ✓ | na | na | ✓ | ✓ | na | |
Bose et al. [51] | tardbp Y220X | ✓ | X | na | na | X | X | na |
tardbpl KO (5 bp deletion with CRISPR/Cas9) | ✓ | X | na | na | X | X | na | |
tardbp Y220X and tardbpl KO (het/hom) | ✓ | ✓ | na | na | ✓ | X | na | |
tardbp Y220X and tardbpl KO (hom/hom) | ✓ | ✓ | na | na | ✓ | ✓ | na | |
Asakawa et al. [85] | Optogenetic WT tdp-43 | ✓ | na | ✓ | na | na | na | na |
Optogenetic WT hTDP-43 | na | na | na | na | X | na | na | |
Optogenetic hTDP-43 A315T | na | na | na | na | ✓ | na | na | |
Rat (Rattus norvegicus) | ||||||||
Zhou et al. [56] | Inducible OE of hTDP-43 M337V (TET-off) | ✓ | na | ✓ | ✓ | ✓ | ✓ | ✓ |
Mouse (Mus musculus) | ||||||||
Shan et al. [133] | WT hTDP-43 OE | ✓ | na | ✓ | ✓ | ✓ | ✓ | X |
Swarup et al. [59] | WT, A315T, G348C KI in TARDBP (BAC) | ✓ | na | ✓ | na | ✓ | na | X |
Arnold et al. [60] | hTDP-43 Q331K OE | ✓ | ✓ | ✓ | ✓ | ✓ | na | ✓ |
hTDP-43 Q331K (low) OE | X | na | na | X | ✓ | na | ✓ (trend) | |
hTDP-43 M337V OE | X | na | na | X | ✓ | na | ✓ (trend) | |
Mitchell et al. [61] | hTDP-43 Q331K OE | ✓ | na | X | ✓ | ✓ | X | ✓ (trend) |
Coexpression of hTDP-43 WT and Q331K | ✓ | na | ✓ | ✓ | ✓ | ✓ | ✓ | |
hTDP-43 A315T OE | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | |
Walker et al. [117], Spiller et al. [118], Altman et al. [136] | Inducible hTDP-43ΔNLS (TET-off) | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ |
Chand et al. [62] | hTDP-43 Q331K OE | ✓ | ✓ | ✓ | na | ✓ | na | ✓ |
Wang et al. [256] | Selective cKO of Tardbp in oligodendrocytes | X | na | ✓ | na | ✓ | ✓ | X |
White et al. [87] | Q331K-equivalent KI in Tardbp (CRISPR/Cas9) | X | X | na | X | X | na | X |
Ebstein et al. [63] | M337V, G298S KI in TARDBP (BAC) | ✓ (hom) | na | na | na | na | na | ✓ |
Gordon et al. [64], Williamson et al. [65], Sleigh et al. [58] | M337V KI in TARDBP (BAC) | ✓ | na | ✓ | ✓ | ✓ | ✓ | X |
White et al. [66] | hTDP-43 Q331K OE | ✓ | na | ✓ | ✓ | ✓ | na | ✓ |
Huang et al. [57] | A315T, N390D-equivalent KI in Tardbp (BAC) | ✓ (N390D) | na | ✓ (N390D) | ✓ (N390D) | ✓ (N390D) | ✓ (N390D) | ✓ (N390D) |
Peng et al. [255] | Selective cKO of Tardbp in astrocytes | X | na | na | na | ✓ | na | X |
Human cell-based models | ||||||||
Osaki et al. [67] | Patient-derived TDP-43 G298S iPSCs differentiated into MN spheroids and co-cultured with WT human iPSC-derived skeletal muscle | ✓ | ✓ | ✓ | ✓ | – | – | ✓ |
Pereira et al. [68] | CRISPR/Cas9-edited TDP-43 G298S iPSCs differentiated into sensorimotor organoids | ✓ | na | X | X | – | – | X |