Tumor necrosis factor receptor-associated protein 1 regulates cell adhesion and synaptic morphology via modulation of N-cadherin expression.
An increase in serum tumor necrosis factor-alpha (TNF-alpha) levels is closely related to the pathogenesis of major depression. However, the underlying molecular mechanism between this increase and impairment of brain function remains elusive. To better understand TNF-alpha/TNF receptor 1 signaling in the brain, we analyzed the brain distribution and function of tumor necrosis factor receptor-associated protein 1 (TRAP1). Here we show that TRAP1 is broadly expressed in neurons in the mouse brain, including regions that are implicated in the pathogenesis of major depression. We demonstrate that small interfering RNA-mediated knockdown of TRAP1 in a neuronal cell line decreases tyrosine phosphorylation of STAT3, followed by a reduction of the transcription factor E2F1, resulting in a down-regulation of N-cadherin, and affects the adhesive properties of the cells. In addition, in cultured hippocampal neurons, reduced expression of N-cadherin by TRAP1 knockdown influences the morphology of dendritic spines. We also report a significant association between several single nucleotide polymorphisms in the TRAP1 gene and major depression. Our findings indicate that TRAP1 mediates TNF-alpha/TNF receptor 1 signaling to modulate N-cadherin expression and to regulate cell adhesion and synaptic morphology, which may contribute to the pathogenesis of major depression.
Kubota
Kyoko
K
Department of Anatomy and Neuroscience, Osaka University Graduate School of Medicine, Suita, Japan.
Inoue
Kiyoshi
K
Hashimoto
Ryota
R
Kumamoto
Natsuko
N
Kosuga
Asako
A
Tatsumi
Masahiko
M
Kamijima
Kunitoshi
K
Kunugi
Hiroshi
H
Iwata
Nakao
N
Ozaki
Norio
N
Takeda
Masatoshi
M
Tohyama
Masaya
M
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D002448:Cell Adhesion / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology*; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure*
D015703:Antigens, CD; C050361:CDH2 protein, human; D015820:Cadherins; D018841:HSP90 Heat-Shock Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; C092306:TRAP1 protein, human