Table 2.
Few overt effects on neuropathology and motor and behavioral phenotypes are seen in overexpression studies of TDP-43 CTFs in mouse, rat, Drosophila, and C. elegans models.
| Model organism | Amino acid sequence of TDP-43 CTF transgene | Promoter/driver | Additional study details | Controls and comparisons | Phenotype measure | Phenotype outcome | Neuropathology | References |
|---|---|---|---|---|---|---|---|---|
| Mouse | 208–414 | CaMKIIα | Dox-suppressible expression. Transgene induced at 1 month of age. Mice examined up to 24 months of age. | NT and monogenic littermates | Rotarod Wirehang Y-maze | No gross motor or cognitive deficits. | CTFs localized to cytoplasm but no large inclusions. CTFs phosphorylated in hippocampal CA1 region but no neurodegeneration. Minimal phosphorylation of CTFs in the dentate gyrus but progressive death of granule cells in mice 10 months and older. | Walker et al., 2015b |
| Insoluble protein extracted from FTLD- TDP brains injected into mouse cortex. | NT and ΔNLS mice | n/a | Mice demonstrated less spread of TDP-43 pathology throughout the brain compared to ΔNLS mice. | Porta et al., 2018 | ||||
| NEFH | Dox-suppressible expression. Transgene induced at 1 month of age. Mice examined up to 19 months of age. | NT and monogenic littermates | n/a | No overt neurodegeneration. TDP-43 phosphorylated in CA1 region of hippocampus, and ubiquitinated in SLM. | Walker et al., 2015b | |||
| Dox-suppressible expression. Transgene induced for 6 weeks in adult mice. | NT | No gross motor defects observed (data not shown). | No motor neuron degeneration, clearance of nuclear TDP-43 or large cytoplasmic inclusions detected in lumbar SC. | Spiller et al., 2018 | ||||
| PrP | Animals examined at 8, 13, and 18 months of age. | FL-TDP-43 and NT | Rotarod Y-maze Contextual and cued fear conditioning | No motor or behavioral phenotype. Mild memory and motor deficits were observed in mice that overexpressed FL-TDP-43. | No change in endogenous TDP-43 levels. | Tsuiji et al., 2017 | ||
| 216–414 | Thy1.2 | Animals examined at 2 or 6 months of age. | NT littermates | Novel object recognition test T-maze Open field locomotion test Rotarod | No significant difference in any behavior or motor tests. | Soluble CTFs detected in cytoplasm and nucleus, by long exposure of immunoblot. No change in endogenous TDP-43 levels and no inclusions or neurodegeneration. | Caccamo et al., 2012 | |
| Mice treated with the glucocorticoid dexamethasone at 6 months of age. | NT | Spatial version of Morris water maze | Dexamethasone treatment worsened memory deficits but had no effect on swim speed or distance traveled, indicating no motor impairment. | In mice expressing CTF-25, dexamethasone treatment impaired autophagy (indicated by lower levels of Atg7 and LC3-II) and increased soluble CTF-25 levels in the nucleus and cytoplasm but no change to endogenous FL-TDP-43 levels. | Caccamo et al., 2013 | |||
| Hemizygous and homozygous mice examined at 15 months of age. | NT | Radial arm water Maze Morris water maze Rotarod | Hemizygous mice exhibited motor dysfunction and impaired spatial and working memory, exacerbated in homozygous mice. | Impaired autophagy and proteosomal function in both lines. Soluble and insoluble CTF-25 detected in the nucleus and cytoplasm, but FL-TDP-43 only detected in the nucleus. Homozygous mice showed lower levels of endogenous FL TDP-43. | Caccamo et al., 2015 | |||
| 219–414 | CMV/chicken β-actin | In utero electroporation of construct into embryonic motor cortex. | FL-TDP-43 and TDP-43M337V | n/a | CTFs formed ubiquitinated, phosphorylated aggregates in nucleus and cytoplasm, detected up to 21 days post-natal. | Akamatsu et al., 2013 | ||
| Rat | 220–414 | CMV/chicken β-actin | IV injection of AAV9 in WT neonatal rats. Animals phenotyped from 2 to 24 weeks of age. | ΔNLS and GFP | Rotarod Open field test Hindlimb extension Locomotor Scoring of rearing behavior | CTF and ΔNLS rats showed equivalent motor dysfunction in rotarod and open field tests. Deficient forelimb use during rearing in seven of 13 CTF and two of 16 ΔNLS rats tested. | No neurodegeneration or muscle atrophy in any of the models examined. | Dayton et al., 2013 |
| Drosophila | 174–414 and 206–414 | elav/Gal4 for pan-neuronal expression, D42/Gal4 for MN expression, DaG32/Gal4 for ubiquitous expression | FL-TDP-43, ΔNLS, and disease-linked mutants (TDP-43A315T, TDP-43G287S, TDP-43A382T, and TDP-43N390D) | Climbing assay Longevity assay | Pan-neuronal or MN specific CTF expression caused a milder reduction in locomotion and lifespan compared to ΔNLS and disease-linked mutants. CTF had no impact on lifespan while other mutants caused premature death. | n/a | Voigt et al., 2010 | |
| 202–414 | GMR-Gal4 for expression in retinal photoreceptors | FL-TDP-43 and RFP | n/a | FL-TDP-43 associated with progressive degeneration and ultrastructural vacuoles in retinal cells, while CTF expression had no effect. | Li et al., 2010 | |||
| NT and FL-TDP-43 | Climbing assay Longevity assay | Compared to FL-TDP-43, expression of CTF caused later onset of motor deficits, which was rescued by treatment with the small heat shock protein CG14207. | CTF-25 was less toxic than FL-TDP-43, produced a milder rough eye phenotype and was cleared more efficiently by CG14207. | Gregory et al., 2012 | ||||
| OK107-Gal4 for expression in mushroom bodies | FL-TDP-43 and RFP | n/a | FL-TDP-43 was associated with neuronal death and loss of axons. No effect of CTF expression. | Li et al., 2010 | ||||
| OK371-Gal4 for MN expression | FL-TDP-43 and RFP | n/a | CTF expression had no effect. Regions where FL-TDP-43 had accumulated in the cytoplasm showed axonal swelling, inclusion formation in soma and axons and fragmentation of the nucleus. | Li et al., 2010 | ||||
| C. elegans | 219–411 | snb-1 for pan-neuronal expression | FL-TDP-43, disease-linked TDP-43Q331K and TDP-43M337V mutants | Fly motility assay | FL-TDP-43 and disease mutants produced more severe motor deficits than expression of the CTF. | CTF formed cytoplasmic aggregates but less toxic to neurons than FL-TDP-43. | Zhang et al., 2011 | |
| 220–411 | snb-1 | Constructs with RMM1, RMM2 or C-terminal deleted | n/a | CTF formed large cytoplasmic inclusions whereas RMM1 and RMM2 mutants had a granular appearance and C-terminal deletion mutant formed a singular aggregate in the cytoplasm. | Ash et al., 2010 | |||
AAV9, adeno-associated virus serotype 9; Atg7, autophagy-related protein 7; C. elegans, Caenorhabditis elegans; CA1, cornu ammonis field 1; CaMKIIα, Ca2+/calmodulin-dependent kinase II α; CMV, cytomegalovirus; CTF; C-terminal fragment; Dox, doxycycline; FL-TDP-43, full-length TDP-43; GFP, green fluorescent protein; IV, intravenous; LC3, microtubule-associated protein 1A/1B-light chain 3; LC3-II, LC3-phosphatidylethanolamine conjugate; MN, motor neuron; NT, non-transgenic; RFP, red fluorescent protein; RRM1, RNA recognition motif 1; RRM2, RNA recognition motif 2; SC, spinal cord; SLM, stratum lacunosum-moleculare; snb-1, synaptobrevin-1; WT, wild-type.