Vcp Overexpression and Leucine Supplementation Increase Protein Synthesis and Improve Fear Memory and Social Interaction of Nf1 Mutant Mice

• Published in: Cell reports (Cambridge) Vol. 31; no. 13; p. 107835
• Main Authors: Shih, Yu-Tzu, Huang, Tzyy-Nan, Hu, Hsiao-Tang, Yen, Tzu-Li, Hsueh, Yi-Ping
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.06.2020; Elsevier
• Subjects: Animals; autism spectrum disorders; Behavior, Animal - drug effects; Brain - drug effects; Brain - physiology; branched-chain amino acids; Cells, Cultured; dendritic spine formation; Dendritic Spines - metabolism; Dendritic Spines - ultrastructure; Dietary Supplements; endoplasmic reticulum; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - ultrastructure; Fear - physiology; leucine; Leucine - administration & dosage; Memory - physiology; Mice, Mutant Strains; neurodevelopmental disorders; neurofibromatosis type 1; neurofibromin; Neurofibromin 1 - metabolism; Neurons - drug effects; Neurons - metabolism; Protein Biosynthesis - drug effects; Proteome - metabolism; Sirolimus - pharmacology; Social Behavior; Synapses - drug effects; Synapses - metabolism; Valosin Containing Protein - metabolism; valosin-containing protein/P97; leucine; valosin-containing protein/P97; neurofibromin; neurofibromatosis type 1; autism spectrum disorders; branched-chain amino acids; neurodevelopmental disorders; endoplasmic reticulum; dendritic spine formation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107835

Neurofibromatosis type 1 (NF1) is a dominant genetic disorder manifesting, in part, as cognitive defects. Previous study indicated that neurofibromin (NF1 protein) interacts with valosin-containing protein (VCP)/P97 to control dendritic spine formation, but the mechanism is unknown. Here, using Nf1+/– mice and transgenic mice overexpressing wild-type Vcp/p97, we demonstrate that neurofibromin acts with VCP to control endoplasmic reticulum (ER) formation and consequent protein synthesis and regulates dendritic spine formation, thereby modulating contextual fear memory and social interaction. To validate the role of protein synthesis, we perform leucine supplementation in vitro and in vivo. Our results suggest that leucine can effectively enter the brain and increase protein synthesis and dendritic spine density of Nf1+/– neurons. Contextual memory and social behavior of Nf1+/– mice are also restored by leucine supplementation. Our study suggests that the “ER-protein synthesis” pathway downstream of neurofibromin and VCP is a critical regulator of dendritic spinogenesis and brain function. [Display omitted] •Neurofibromin and VCP act together to regulate ER formation and protein synthesis•VCP overexpression improves neuronal and behavioral defects of Nf1+/– mice•Leucine supplementation ameliorates neuronal and behavioral defects of Nf1+/– mice Shih et al. show that neurofibromin (NF1 protein) acts through valosin-containing protein (VCP)/p97 to regulate endoplasmic reticulum formation and protein synthesis. It consequently controls dendritic spine formation and contextual and social memory of mice. Increased protein synthesis through leucine supplementation ameliorates neuronal and behavioral defects of Nf1 mutant mice.