| First Author | Gao J | Year | 2021 |
| Journal | J Cell Biol | Volume | 220 |
| Issue | 10 | PubMed ID | 34427634 |
| Mgi Jnum | J:337808 | Mgi Id | MGI:7261102 |
| Doi | 10.1083/jcb.202101019 | Citation | Gao J, et al. (2021) Translational regulation in the brain by TDP-43 phase separation. J Cell Biol 220(10):e202101019 |
| abstractText | The in vivo physiological function of liquid-liquid phase separation (LLPS) that governs non-membrane-bound structures remains elusive. Among LLPS-prone proteins, TAR DNA-binding protein of 43 kD (TDP-43) is under intense investigation because of its close association with neurological disorders. Here, we generated mice expressing endogenous LLPS-deficient murine TDP-43. LLPS-deficient TDP-43 mice demonstrate impaired neuronal function and behavioral abnormalities specifically related to brain function. Brain neurons of these mice, however, did not show TDP-43 proteinopathy or neurodegeneration. Instead, the global rate of protein synthesis was found to be greatly enhanced by TDP-43 LLPS loss. Mechanistically, TDP-43 LLPS ablation increased its association with PABPC4, RPS6, RPL7, and other translational factors. The physical interactions between TDP-43 and translational factors relies on a motif, the deletion of which abolished the impact of LLPS-deficient TDP-43 on translation. Our findings show a specific physiological role for TDP-43 LLPS in the regulation of brain function and uncover an intriguing novel molecular mechanism of translational control by LLPS. |
