Table 2 Summary of studies used in the mouse proteomics meta-analysis.

Mouse model

TDP-43 regulatable NLS8 (doxycycline (dox)-dependent inhibition of human cytoplasmic TDP-43 transgene)

Tissue type

Cortex

Sex

Female

Age

From 10 weeks of age

Experimental groups

1. Pre-onset—1 week off dox

2. Onset – 2 weeks off dox

3. Early disease – 4 weeks off dox

4. Late disease – 6 weeks off dox

5. Recovery – 6 weeks off dox and 2 weeks on dox

Phenotype

- Motor deficits emerge at early disease (4 weeks) with a decrease in muscle innervation, cortical neuron degeneration and astrogliosis

- At late disease (6 weeks) there is microglial dysfunction, spinal cord motor neuron degeneration and a dramatic motor deficit

- Mice in recovery show clearance of cytoplasmic TDP-43, restoration of endogenous TDP-43 in neurons, muscle re-innervation from remaining neurons, and regain motor skills

Mouse model

1. TDP-43: B6;129S6Gt(ROSA)26Sortm1-(TARDBP*M337V/Ypet)Tlbt/J mice

2. SOD1: B6SJL-Tg(SOD1*G93A)1Gur/J mice

3. C9orf72: (Poly)GA-NES/C9orf72(R26(CAG-Isl-175GA) − 29 × Nes-Cre mice

4. FUS: Tg (Prnp-FUS)WT3Cshw/J mice

Tissue type

Pre-frontal cortex

Sex

Female & male

Age

1. 26 weeks

2. 14 weeks

3. 4.5 weeks

4. 4 weeks

Experimental groups

Female & male:

1. TDP-43

2. SOD1

3. C9orf72

4. FUS

Phenotype

- Pre-symptomatic stages (TDP-43 & SOD1 mice)

- Early symptomatic (C9orf72)

Mouse model

1. FUS: ΔFUS(1–359) mice

2. TDP-43: B6.Cg-Tg(Prnp-TARDBP*A315T)95Balo/J)

Tissue type

Cortex

Sex

1. Female & male

2. Male

Age

1. PND 49–51

2. PND 57–62

Experimental groups

1. FUS

2. TDP-43

Phenotype

Presymptomatic

Mouse model

1. Ubqln2 KO mice (generated by insertion of loxP sites flanking the one exon of murine Ubqln2)

2. Ubqln2 KI containing mutant murine P520T Ubqln2 allele corresponding to the human disease-causing P506T mutation

Tissue type

Brain, lumbar spinal cord or hippocampus

Sex

Male

Age

1. Young (4–6 months) and old (12–16 months)

2. Young (4–6 months)

Experimental groups

1. Ubqln2 KO brain – young mice

2. Ubqln2 KO brain – old mice

3. Ubqln2 KO hippocampus – young mice

4. Ubqln2 KO spine – young mice

5. Ubqln2 KI hippocampus – young mice

6. Ubqln2 KI spine – young mice

Phenotype

Animals have an intermediate, age-dependent neuromotor disease (10–14 months old) more severe than that seen in Ubqln2 knock-in mice

Mouse model

B6N.Cg-Tg(Prnp-TARDBP*Q331K)-

103Dwc/J mice

Tissue type

Brain or spine

Sex

Female

Age

PND 180

Experimental groups

1. Brain from TDP-43 mice

2. Spine from TDP-43 mice

3. Brain & spine (computationally merged)

Phenotype

- Enhanced cytoplasmic mutant TDP-43 expression from 8 weeks old

- Progressive motor dysfunction beginning at 3 months of age

- A 43% reduction in hindlimb muscle mass by 6 months¹²