From: From animal models to human disease: a genetic approach for personalized medicine in ALS
Species | Mutation | Promoter (fold expression) | Age at onset (weeks) | Survival (weeks) | Phenotype | References | |||
---|---|---|---|---|---|---|---|---|---|
Paralysis | Cognitive symptoms | Neuropathological findings and particularities | Gliosis | ||||||
Mice | hTDP-43WT | mPrp (3–4) | None | Normal | N | nd | Diffuse ubiquitin staining, no NCI | mild | [262] |
 |  | mPrp (2.5) a | 3 | 4–8 | Y | nd | pTDP-43 NCI, cytosolic ubiquitination, axonal degeneration, no MN loss | Y | [135] |
 |  | mThy1.2(3.8–5.1) | 2–8 | 4–27 | Y | nd | Rapid disease progression, rare pTDP-43 NCI, MN loss, phenotype correlates with protein level | Y | [263] |
 |  | mThy1.2(1.3–3.6) | Males: 2 Females: 13 | nd | nd | nd | Mitochondrial aggregation, no TDP-43 NCI, decreased axon caliber, no MN loss | nd | [264] |
 |  | mCaMKIIc (0.4–1.7) | 4 | nd | nd | nd | Brain atrophy, Neuron loss, mosaic expression, rare pTDP-43 NCI | Y | [265] |
 |  | CAG | None | Normal | N | nd | No motor impairment, neuron loss in frontal cortex, no NCI | nd | [266] |
 |  | hEP (3) | 42 | Normal | N | Y | No TDP-43/ubiquitin NCI, motor dysfunction without paralysis | Y | [138] |
 | mTDP-43WT | mCaMKII(2)a | 8 | 71 | N | Y | Learning/memory deficit, TDP-43/ubiquitin positive NCI, progressive motor deficits | Y | [267] |
 | A315T\ | mPrp (4) | 4 | 10.7 | Y | nd | Rare pTDP-43 NCI, no GCI, MA | Y | [134] |
 |  | mPrp (3) | 12–16 | 22 ± 2.7 | Y | nd b | Ubiquitin positive/TDP-43 negative NCI, UMN/LMN loss | Y | [139] |
 |  | hEP (3) | 38 | Normal | N | Y | TDP-43+/Ubiquitin + NCI at 10 months, peripherin inclusions, decrease axonal caliber, motor dysfunction without paralysis | Y | [138] |
 |  | mEP (2.5)d | nd | nd | nd | N | TDP-43 NCI, 10 % MN loss | nd | [268] |
 | Q331K | mPrp (1.5) | 12 | Normal | N | nd | Decreased motor performance at 10 months, muscle fibrillations at EMG, No NCI | Y | [140] |
 | WT/Q331K | mPrp (3.3) | 3 | 8–10 | Y | nd | TDP-43/ubiquitin/p62 NCI, 70 % MN loss in SC anterior horn | Y | [141] |
 | M337V | mPrp (2.7)a | 3 | 4 | Y | nd | Tremors, pTDP-43 NCI, cytosolic ubiquitination, no MN loss, MA | Y | [269] |
 |  | mPrp (1.5) | 40 | Normal | N | nd | Decreased motor performance at 10 months, no NCI | nd | [140] |
 |  | Thy1.2 (1.7)a | <2 | 2,5 | Y | nd | Ubiquitin/TDP-43 NCI, worse phenotype than TDP-43WT mouse | Y | [270] |
 | G348C | hEP (3) | 36 | Normal | N | Y | TDP-43+/Ubiquitin+ NCI at 10 months, peripherin inclusions, decreased axonal caliber, motor dysfunction without paralysis | Y | [138] |
Rats | hTDP-43WT | hEP (nd) | Normal | Normal | N | nd | Normal | nd | [142] |
 | M337V | hEP (nd) | 2–3 | 1.5–4 | Y | nd | Loss of MN in ventral horn | nd | [142] |
 | M337V | TRE (nd) PN day 4 | 3 | 5 | Y | nd | Degeneration of ventral root, dorsal root and corticospinal tract, pTDP-43 staining, but no NCI | Y | [142] |
 |  | TRE-NFH(nd) PN day 60 | 10 | nd | Y | nd | Paralysis within 3 weeks, no TDP-43 NCI, motor function restores with removal of TDP-43 | Y | [143] |
 |  | TRE-GFAP(1.3) PN day 40 | 8.6 | 11.4 | Y | nd | MN loss, MA, | nd | [271] |
Fruit flies | hTDP-43WT | OK371-Gal4e (nd) | 10Â days | nd | N | nd | TDP-43 inclusions, MN loss, larval motility deficit | nd | [272] |
 |  | D42-Gal4e(nd) | 2–3 | 2.5–3.5 | Y | nd | Progressive motor deficit leading to paralysis, no NCI | nd | [145] |
 |  | GAL4-UAS(nd) | nd | nd | Y | nd | Dose-dependent cytosolic TDP-43 and NCI, decreased larvae and adult movement, decreased NMJ | nd | [148] |
 | WT, Q331K | MN (nd) | nd | nd | nd | nd | Motor deficits, Q331K had worst phenotype | nd | [273] |
 | WT, F147L/F149L, G287S, A315T, G348C, A382T, ΔNLS | D42-Gal4e(nd) | 10–20 days | 20–40 days | Y | nd | Progressive loss of motor performance, worse phenotype seen in WT, MN loss | nd | [146] |
 | dTDP-43 | D42TS-Gal4f(nd) | 12–14 days | 23 days | N | nd | Decreased thoracic number of neurons, locomotor defect, shorter lifespan | nd | [147] |
Nematodes | TDP-1, hTDP-43WT | snb-1 | larvae | nd | N | nd | No NCI, slow movement | nd | [149] |
 | hTDP-43WT, G290A, A315T, M337V | snb-1 | nd | 13–18.9 days | Y | nd | Lethargy, flattened sinusoidal waveform and reduced locomotion, worse phenotype with mutations, pTDP-43, ubiquitin, no NCI, nuclear aggregates | nd | [150] |
 | hTDP-43WT, A315T | unc-47 | 4–6 days | normal | Y | nd | GABAergic motor neurons expression, older paralysis in WT (20 days) as compared to A315T (12–13 days), MN loss, cytoplasmic TDP-43 | nd | [207] |
Zebrafish | hTDP-43WT, A315T, G348C, A382T | mRNAs | 24 hpf | nd | Y | nd | Motor deficit, phenotype was mRNA concentration dependant, worse phenotype in mutant, decreased motor axons length | nd | [151] |
 | hTDP-43WT, A315T | mRNAs | 28 hpt | nd | nd | nd | Reduced axonal length in A315T | nd | [152] |