期刊
JOURNAL OF CELL BIOLOGY
卷 220, 期 10, 页码 -出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.202101019
关键词
-
类别
资金
- National Institutes of Health [1R01NS089604, R01NS097679, RF1AG056320]
- Alzheimer's Association [AARG-17-499682]
The study found that TDP-43 LLPS plays a specific physiological role in regulating brain function and revealed a novel molecular mechanism of translational control through LLPS.
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.
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