Neurochondrin Negatively Regulates CaMKII Phosphorylation, and Nervous System-specific Gene Disruption Results in Epileptic Seizure

Dateki, Minori; Horii, Takuro; Kasuya, Yoshitoshi; Mochizuki, Reiko; Nagao, Yoshimi; Ishida, Junji; Sugiyama, Fumihiro; Tanimoto, Koichi; Yagami, Ken‐ichi; Imai, Haruo; Fukamizu, Akiyoshi

doi:10.1074/jbc.m414033200

Cited by 46 publications

(44 citation statements)

References 29 publications

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“…6B and 7B]). Other genes that remained downregulated during infection were neurochondrin (NCDN), involved in neurite outgrowth (40); complexin 1 (CPLX1), expressed by neurons and regulating synaptic vesicle exocytosis (41) (confirmed by IHC and qRT-PCR [ Fig. 6C and 7C]); and progestin and adipoQ receptor 6 (PAQR6) a G-coupled membrane progesterone receptor that exhibits neuroprotective properties (42) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia

Arnold

Girke

Sureshchandra

et al. 2016

J Virol

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Primary infection with varicella-zoster virus (VZV), a neurotropic alphaherpesvirus, results in varicella. VZV establishes latency in the sensory ganglia and can reactivate later in life to cause herpes zoster. The relationship between VZV and its host during acute infection in the sensory ganglia is not well understood due to limited access to clinical specimens. Intrabronchial inoculation of rhesus macaques with simian varicella virus (SVV) recapitulates the hallmarks of VZV infection in humans. We leveraged this animal model to characterize the host-pathogen interactions in the ganglia during both acute and latent infection by measuring both viral and host transcriptomes on days postinfection (dpi) 3, 7, 10, 14, and 100. SVV DNA and transcripts were detected in sensory ganglia 3 dpi, before the appearance of rash. CD4 and CD8 T cells were also detected in the sensory ganglia 3 dpi. Moreover, lung-resident T cells isolated from the same animals 3 dpi also harbored SVV DNA and transcripts, suggesting that T cells may be responsible for trafficking SVV to the ganglia. Transcriptome sequencing (RNA-Seq) analysis showed that cessation of viral transcription 7 dpi coincides with a robust antiviral innate immune response in the ganglia. Interestingly, a significant number of genes that play a critical role in nervous system development and function remained downregulated into latency. These studies provide novel insights into host-pathogen interactions in the sensory ganglia during acute varicella and demonstrate that SVV infection results in profound and sustained changes in neuronal gene expression. IMPORTANCEMany aspects of VZV infection of sensory ganglia remain poorly understood, due to limited access to human specimens and the fact that VZV is strictly a human virus. Infection of rhesus macaques with simian varicella virus (SVV), a homolog of VZV, provides a robust model of the human disease. Using this model, we show that SVV reaches the ganglia early after infection, most likely by T cells, and that the induction of a robust innate immune response correlates with cessation of virus transcription. We also report significant changes in the expression of genes that play an important role in neuronal function. Importantly, these changes persist long after viral replication ceases. Given the homology between SVV and VZV, and the genetic and physiological similarities between rhesus macaques and humans, our results provide novel insight into the interactions between VZV and its human host and explain some of the neurological consequences of VZV infection. V aricella-zoster virus (VZV) is a neurotropic alphaherpesvirus and the causative agent of varicella (chickenpox) (1). VZV establishes latency in the sensory ganglia and can reactivate later in life to cause herpes zoster (shingles), a painful disease that affects almost 1 million individuals in the United States alone (2). VZV is transmitted through the inhalation of virus-laden saliva droplets or by direct contact with the infectious fluid from vesicles...

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Section: Resultsmentioning

confidence: 99%

Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia

Arnold

Girke

Sureshchandra

et al. 2016

J Virol

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“…Given that Rab5 is required for internalization of AMPAR during long term depression (52), Ncdn might regulate internalization of AMPAR, directly acting on early endosome dynamics or indirectly modulating a signal through mGluR5. Because conditional Ncdn KO mice showed apparent pathological phenotypes (epileptic seizures and schizophreniarelevant behaviors) (23,24), genetic experiments using knock-in mice in which Ncdn palmitoylation-deficient mutant is expressed should reveal the roles of Ncdn palmitoylation in these pathophysiological phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…GPCR, G-protein coupled receptors predominantly expressed in the brain, has a very high CSSPalm score (Fig. 1C, Table 1, and supplemental Table S2), and plays an important role in neurite outgrowth (20,48) and synaptic plasticity (20,23,24). Thus, we subsequently focused on Ncdn palmitoylation.…”

Section: Examination Of Novel Palmitoyl Substrates By Experimentalmentioning

confidence: 99%

“…KO of Ncdn in mice leads to early embryonic lethality (22). Nervous system-specific conditional KO of Ncdn in mice results in epileptic seizure (23). Forebrain-specific Ncdn KO attenuates metabotropic glutamate receptor 5 (mGluR5)-dependent stable change in synaptic transmission in the hippocampus and results in a behavioral phenotype associated with a rodent model of schizophrenia (24).…”

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confidence: 99%

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In Silico Screening for Palmitoyl Substrates Reveals a Role for DHHC1/3/10 (zDHHC1/3/11)-mediated Neurochondrin Palmitoylation in Its Targeting to Rab5-positive Endosomes

Oku

Takahashi

Fukata

et al. 2013

Journal of Biological Chemistry

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Background:The identification of palmitoyl substrate-enzyme pairs is important for elucidating physiological roles of protein palmitoylation. Results: In silico screening revealed neurochondrin palmitoylation. DHHC1/3/10 were identified as neurochondrin palmitoylating enzymes and were essential for targeting of neurochondrin to Rab5-positive endosomes. Conclusion: Neurochondrin and the DHHC1/10 and DHHC3/7 subfamilies represent novel substrate-enzyme pairs. Significance: In silico palmitoyl screening is useful for clarifying functions of palmitoylation.

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“…It has been reported that the expression of CaMKII mRNA is increased after kindling and status epilepsy. Neurochondrin conditional knockout mice show up-regulated activity of CaMKII and high susceptibility to epilepsy [24] .…”

Section: Altered Expression Of Fmrp's Target Mrnas May Exert a Pro-efmentioning

confidence: 99%

Fragile X syndrome and epilepsy

et al. 2008

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Fragile X syndrome (FXS) is one of the most prevalent mental retardations. It is mainly caused by the loss of fragile X mental retardation protein (FMRP). FMRP is an RNA binding protein and can regulate the translation of its binding RNA, thus regulate several signaling pathways. Many FXS patients show high susceptibility to epilepsy. Epilepsy is a chronic neurological disorder which is characterized by the recurrent appearance of spontaneous seizures due to neuronal hyperactivity in the brain. Both the abnormal activation of several signaling pathway and morphological abnormality that are caused by the loss of FMRP can lead to a high susceptibility to epilepsy. Combining with the research progresses on both FXS and epilepsy, we outlined the possible mechanisms of high susceptibility to epilepsy in FXS and tried to give a prospect on the future research on the mechanism of epilepsy that happened in other mental retardations.

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Neurochondrin Negatively Regulates CaMKII Phosphorylation, and Nervous System-specific Gene Disruption Results in Epileptic Seizure

Cited by 46 publications

References 29 publications

Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia

Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia

In Silico Screening for Palmitoyl Substrates Reveals a Role for DHHC1/3/10 (zDHHC1/3/11)-mediated Neurochondrin Palmitoylation in Its Targeting to Rab5-positive Endosomes

Fragile X syndrome and epilepsy

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