Table 13.
Gain-of-function phenotypes induced by ALS-linked TDP-43 mutants.
| TDP-43 Mutant |
Gal4 Line | Phenotype/Reference |
|---|---|---|
| D169G | D42-Gal4 (motoneurons) |
Decreased bouton number [336] Increased active zone number [336] Increased larval turning time [331,336] Abnormal nuclear shape [336] |
| Repo-Gal4 (pan-glial) |
Normal bouton number (reduced with WT) [336] Normal active zone number [336] Increased GluRIIC [336] Increased larval turning time [336] |
|
| GMR-Gal4 (eye) |
Age and dose dependent degeneration [331,336] | |
| G287S | Act5C-Gal4 (ubiquitous) | Lethal [305] |
| Elav-Gal4 (pan-neuronal) |
Viable, reduced lifespan (as WT but better) [305] | |
| G298S | Elav-Gal4 (pan-neuronal) |
Impaired climbing [311] |
| D42-Gal4 (motoneurons) |
Decreased bouton number [336], (normal with WT) [293] Increased active zone number [336] Abnormal nuclear shape [336] Increased larval turning time [317,318,319,331,336,340], (normal with WT) [293] Decreased larval locomotion (Normal with WT) [293] Reduced lifespan [318], (as WT but worse) [293] |
|
| Repo-Gal4 (pan-glial) |
Decreased bouton number [336] Normal number of active zones [336] Increased GluRIIC [336] Increased larval turning time [336] |
|
| GMR-Gal4 (eye) |
Degeneration [317,318,319] Age- and dose-dependent degeneration [336] Age-dependent degeneration (as WT but worse) [293] |
|
| A315T | Act5C-Gal4 (ubiquitous) | Lethal [305] |
| Elav-Gal4 (pan-neuronal) |
Viable, reduced lifespan (as WT but better) [305] | |
| Elav-Gal4, Tubulin-Gal80TS (pan-neuronal, induced at adult stage) |
Age-dependent climbing deficit (as WT but worse) [312] | |
| D42-Gal4 (motoneurons) |
No change in bouton number (WT decreased) [289], decreased at high dose [289,336] No change in branch number, even at high dose (WT decreased) [289] Increased larval turning time (as WT but worse) [289] Increased active zone number [336] Abnormal nuclear shape [336] Viable but 100% pupal lethal at high dose (WT semi-lethal, escapers) [289] Reduced lifespan (as WT but better) [289] Impaired climbing (as WT but better) [289] No motoneuron apoptosis in LIII ganglia [289] Rare motoneuron apoptosis in adult thoracic ganglia (as WT but better) [289] Age progressive climbing deficit [305] Upregulation of HDAC6 mRNA (as WT but more) [340] |
|
| OK371-Gal4 (glutamatergic neurons) |
Cell soma and proximal axon (WT reaches distal axon and NMJ) [296] Impaired anterograde movement (compared to WT) [296] |
|
| Repo-Gal4 (pan-glial) |
Normal number of active zones [336] Increased GluRIIC [336] |
|
| GMR-Gal4 (eye) |
Age- and dose-dependent degeneration [289,331], (as WT but worse) [293] Degeneration with mitochondrial damage [312] |
|
| GMR-Gal4, Tubulin-Gal80TS (eye, induced at adult stage) |
Age-dependent degeneration with mitochondrial damage [312] | |
| Q331K | Daughterless-Gal4 (ubiquitous) | Lethal pupal [306] |
| Elav-Gal4 (pan-neuronal) |
Embryonic lethal [306] | |
| D42-Gal4 (motoneurons) |
Age progressive climbing deficit (as WT but worse) [308] | |
| OK371-Gal4 (glutamatergic neurons) |
Lethal [306] | |
| OK371-Gal4/MARCM (individual leg motoneuron) |
Degeneration of leg motor axon and NMJ (as WT but worse) [291] | |
| 24B-Gal4 or Mef2-Gal4 (muscles) |
Lethal [306] | |
| GMR-Gal4 (eye) |
Cytoplasmic puncta (not observed with WT) [306] | |
| Gal4221-Gal4 (sensory neurons) |
Increased dendritic branching (as WT but less) [274] | |
| OK107-Gal4 (mushroom bodies) |
Lethal (WT is viable) [306] | |
| TH-Gal4 (dopaminergic neurons) | Viable [306] | |
| Vestigial-Gal4 (wing imaginal discs) | Ectopic production of scutellar bristle (as WT but less) [287] | |
| M337V | Armadillo-Gal4 (ubiquitous) |
No rescue of viability of TBPH mutant (rescue with WT) [296] |
| Daughterless-Gal4 (ubiquitous) |
Lethal pupal [306] | |
| Elav-Gal4(pan-neuronal) | Embryonic lethal [306] | |
| D42-Gal4 (motoneurons) |
Normal bouton number [293] Increased larval turning time (normal with WT) [293] Decreased larval locomotion (normal with WT) [293] Reduced lifespan (as WT but worse) [293] |
|
| OK371-Gal4 (glutamatergic neurons) |
Cell soma and proximal axon (WT reaches distal axon and NMJ) [296] Impaired anterograde movement (compared to WT) [296] Lethal [306] |
|
| OK6-Gal4 (motoneurons) | Normal bouton number (increased with WT) [159] | |
| 24B-Gal4 or Mef2-Gal4 (muscles) |
Lethal [306] | |
| GMR-Gal4 (eye) |
Age dependent degeneration (as WT but worse) [293,334] | |
| CCAP-Gal4 (bursicon neurons) |
Impaired vesicle transport (no effect with WT) [341] | |
| Gal4221-Gal4 (sensory neurons) |
Increased dendritic branching (as WT but less) [274] | |
| OK107-Gal4 (mushroom bodies) |
Viable [306] | |
| TH-Gal4 (dopaminergic neurons) | Viable [306] | |
| Vestigial-Gal4 (wing imaginal disc) | Ectopic production of scutellar bristle (as WT but less) [287] | |
| Q343R | GMR-Gal4 (eye) |
Age-dependent degeneration (as WT but worse) [293] |
| N345K | D42-Gal4 (motoneurons) |
Decreased bouton number [336] Increased active zone number [336] Increased larval turning time [336] Abnormal nuclear shape [336] |
| Repo-Gal4 (pan-glial) |
Decreased bouton number [336] Normal number of active zones [336] Increased GluRIIC [336] Increased larval turning time [336] |
|
| GMR-Gal4 (eye) |
Age- and dose-dependent degeneration [336] | |
| G348C | Act5C-Gal4 (ubiquitous) | Lethal [305] |
| Elav-Gal4 (pan-neuronal) |
Viable, reduced lifespan (as WT but better) [305] | |
| A382T | Act5C-Gal4 (ubiquitous) | Lethal [305] |
| Elav-Gal4 (pan-neuronal) |
Viable, reduced lifespan (as WT but better) [305] | |
| D42-Gal4 (motoneurons) |
Upregulation of HDAC6 mRNA (as WT but more) [340] | |
| N390D | Act5C-Gal4 (ubiquitous) | Lethal [305] |
| Elav-Gal4 (pan-neuronal) |
Viable, reduced lifespan (as WT but better) [305] |
Most of the phenotypes induced by ALS-linked TDP-43 mutants are similar to those induced by wildtype except when mentioned (text in bold). Note that studies that used ALS-linked mutants without comparing them to the wildtype are not mentioned.