| First Author | Ke YD | Year | 2024 |
| Journal | Neuron | Volume | 112 |
| Issue | 8 | Pages | 1249-1264.e8 |
| PubMed ID | 38366598 | Mgi Jnum | J:348663 |
| Mgi Id | MGI:7623048 | Doi | 10.1016/j.neuron.2024.01.022 |
| Citation | Ke YD, et al. (2024) Targeting 14-3-3theta-mediated TDP-43 pathology in amyotrophic lateral sclerosis and frontotemporal dementia mice. Neuron 112(8):1249-1264.e8 |
| abstractText | Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by cytoplasmic deposition of the nuclear TAR-binding protein 43 (TDP-43). Although cytoplasmic re-localization of TDP-43 is a key event in the pathogenesis of ALS/FTD, the underlying mechanisms remain unknown. Here, we identified a non-canonical interaction between 14-3-3theta and TDP-43, which regulates nuclear-cytoplasmic shuttling. Neuronal 14-3-3theta levels were increased in sporadic ALS and FTD with TDP-43 pathology. Pathogenic TDP-43 showed increased interaction with 14-3-3theta, resulting in cytoplasmic accumulation, insolubility, phosphorylation, and fragmentation of TDP-43, resembling pathological changes in disease. Harnessing this increased affinity of 14-3-3theta for pathogenic TDP-43, we devised a gene therapy vector targeting TDP-43 pathology, which mitigated functional deficits and neurodegeneration in different ALS/FTD mouse models expressing mutant or non-mutant TDP-43, including when already symptomatic at the time of treatment. Our study identified 14-3-3theta as a mediator of cytoplasmic TDP-43 localization with implications for ALS/FTD pathogenesis and therapy. |
