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Table 4 TDP-43 animal models

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) 10 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]
  1. Y yes, N no, nd not described, MA muscle atrophy, NCI neuron cytoplasmic inclusion, GCI glial cytoplasmic inclusion, hEP human endogenous promoter, mEP mouse endogenous promoter, MN motor neuron, PN post-natal, hpf hours post-fertilization. Models in bold filled most of the quality criterias (see in main text)
  2. aHomozygotes
  3. bUbiquitin inclusions were observed in cortex but not cognitive evaluation was realized
  4. cTRE induction 28 days after birth
  5. dKnock-in mice
  6. eMotor neuron expression
  7. fdTDP-43 expressed only at higher temperature