Table 5 Mimicking or preventing TDP-43 phosphorylation in different model system
From: Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration
Mimic/ablated sites | Model | Aggregation | Localisation | Neurotoxicity | Other | Reference |
|---|---|---|---|---|---|---|
In vitro | ||||||
S48 | HEK293 | ← S48E disrupts TDP-43 LLPS and oligomerisation | NR | NR | NR | Wang et al. 2018 [33] |
379, 403, 404, 409, 410 | HEK293, Neuro2a | ← 5SD ↓ aggregation and ↑ solubility, 5SA ↑ aggregation and ↓ solubility of C-terminal TDP-43 fragment | NR | NR | NR | Li et al. 2011 [31] |
S48 | Recombinant protein | S48E disrupts TDP-43 LLPS and oligomerisation | NR | NR | NR | Wang et al. 2018 [33] |
T88, S91, S92 | Recombinant protein | → Phosphomimic at T88/S91/S92 ↓ affinity for importin α1/β | NR | NR | Doll et al. 2022 [62] | |
S373, S375, S379, S387, S389, S393, S395, S403, S404, S407, S409, S410 | Recombinant protein | ← CK1δ and 2A, 5A, and 12A condensates have aggregate-like morphology ← 2D, 5D, and 12D condensates are more dynamic and ↓ aggregation | NR | NR | - 12D and 12 A does not impair RNA regulation | Gruijs da Silva et al. 2022 [34] |
S373, S375, S379, S387, S389, S393, S395, S403, S404, S407, S409, S410 | HeLa | ← 12SD ↑solubility | - 12SD and 12SA no change in localisation or nuclear import rate | NR | - 12SD and 12SA does not impact TDP-43 autoregulating its own mRNA or splicing regulation | Gruijs da Silva et al. 2022 [34] |
S373, S375, S379, S387, S389, S393, S395, S403, S404, S407, S409, S410 | U2OS | NR | - 12SD and 12SA no change in localisation | NR | - 12SD and 12SA does not impact TDP-43 autoregulating its own mRNA | Gruijs da Silva et al. 2022 [34] |
S373, S375, S379, S387, S389, S393, S395, S403, S404, S407, S409, S410 | Primary neurons | ← 12SD ↓ insoluble TDP-43 | ← 12SD ↑ TDP-43 dispersal | NR | - 12SD suppresses stress granule recruitment | Gruijs da Silva et al. 2022 [34] |
T153, Y155 | HeLa | ← pT153/Y155 increases TDP-43 solubility from heat shock | - pTDP-43 at T153/Y155 recruited to nucleoli | NR | ← pT153/Y155 reduces TDP-43 regulation of splicing by 30% compared to WT and T153E/Y155 A | Li et al. 2017[32] |
T153, Y155 | SH-SY5Y | - pT153/Y155 did not influence aggregation from heat shock | NR | NR | NR | Li et al. 2017[32] |
Y43 | SH-SY5Y | NR | NR | NR | ← Y43E ↑ G3BP1-positive stress granules | Lee et al. 2022[29] |
Y43 | Primary cortical neurons | NR | → Y43E ↑ TDP-43 cytoplasmic localisation | NR | NR | Lee et al. 2022[29] |
Y43 | Cultured cortical neurons from c-Abl WT or knockout mice | → Y43E ↓ solubility in c-Abl WT or K/O | NR | → Y43E ↑ neuronal cell death in c-Abl K/O model | NR | Lee et al. 2022[29] |
S409, S410 | Cultured neurons | NR | NR | → S409/410A ↓ neuronal injury from OxyHb treatment | NR | Sun et al. 2018[21] |
in vivo | ||||||
S409, S410 | C. elegans | NR | NR | - 2SA with M337V TDP-43 and PP2B knockout did not alter neurodegeneration | - 2SA with M337V TDP-43 and PP2B knockout does not cause locomotion dysfunction | Liachko et al. 2016 [122] |
379, 403, 404, 409, 410 | Drosophila | ← 5SE ↓ aggregates and ↑ solubility | NR | NR | NR | Li et al. 2011 [31] |
S4109, 410 | IHC rats | NR | → S409A/S410A ↓ cytoplasmic mislocalisation | → S409A/S410A ↓autophagy | NR | Sun et al. 2018[21] |