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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