Densin-180 is a transmembrane protein that tightly associated with the postsynaptic density in CNS neurons and postulated to function as synaptic adhesion molecule. Here we report identification of α-subunit Ca 2+ /calmodulin-dependent kinase II (CaMKII) α-actinin-4 potential binding partners for densin-180 intracellular segment. We demonstrate by yeast two-hybrid biochemical assays portion densin-180, CaMKII (CaMKIIα), α-actinin interact each other at distinct sites can form ternary complex...

Activation of CD8 + cytotoxic T cells has long been regarded as a major antitumor mechanism the immune system. Emerging evidence suggests that CD4 are required for generation and maintenance effective memory cells, phenomenon known T-cell help. help facilitates optimal expansion, trafficking, effector function thereby enhancing tumor destruction. In addition, specialized subset CD25 regulatory (T Regs ), effectively hampers anti-tumor responses, which proposed to be one evasion mechanisms....

Inflammation is a potential risk factor of mental disturbance. FKBP5 that encodes FK506-binding protein 51 (FKBP51), negative cochaperone glucocorticoid receptor (GR), stress-inducible gene and has been linked to psychiatric disorders. Yet, the role FKBP51 in inflammatory stress-associated disturbance remained unclear.Fkbp5-deficient (Fkbp5-KO) mice were used study stress by single intraperitoneal injection lipopolysaccharide (LPS). The anxiety-like behaviors, neuroimaging,...

Abstract Episodic ataxia type 2 (EA2) is an autosomal dominant neurological disorder associated with mutations in the gene encoding pore‐forming α 1A subunits of human P/Q‐type calcium (Ca V 2.1) channels. The exact mechanism how mutant channels cause such clinical EA2 features as cerebellar dysfunctions, however, remains unclear. Our previous functional studies Xenopus oocytes support idea that mutants may exert prominent dominant‐negative effects on wild‐type Ca 2.1 To further pursue...

KCND3 encodes the voltage-gated potassium channel KV4.3 that is highly expressed in cerebellum, where it regulates dendritic excitability and calcium influx. Loss-of-function mutations have been associated with dominant spinocerebellar ataxia (SCA19/22). By targeted NGS sequencing, we identified two novel missense variants of channel: p.S347W a patient adult-onset pure cerebellar syndrome p.W359G detected child congenital nonprogressive ataxia. Neuroimaging showed mild atrophy both patients....

Abstract Mammalian Eag1 (Kv10.1) potassium (K + ) channels are widely expressed in the brain. Several mutations gene encoding human K channel have been associated with congenital neurodevelopmental anomalies. Currently very little is known about molecules mediating protein synthesis and degradation of channels. Herein we aim to ascertain mechanism rat (rEag1). We identified cullin 7 (Cul7), a member cullin-based E3 ubiquitin ligase family, as novel rEag1 binding partner. Immunoprecipitation...

Mutations in the human voltage-gated K+ channel subunit KV 4.3-encoding KCND3 gene have been associated with autosomal dominant neurodegenerative disorder spinocerebellar ataxia types 19 and 22 (SCA19/22). The precise pathophysiology underlying inheritance pattern of SCA19/22 remains elusive. Using cerebellar ataxia-specific targeted next-generation sequencing technology, we identified two novel mutations, c.950 G>A (p.C317Y) c.1123 C>T (p.P375S) from a cohort inherited ataxias Taiwan....

Voltage-gated ClC-2 channels are essential for chloride homeostasis. Complete knockout of mouse leads to testicular degeneration and neuronal myelin vacuolation. Gain-of-function loss-of-function mutations in the ClC-2-encoding human CLCN2 gene linked genetic diseases aldosteronism leukodystrophy, respectively. The protein homeostasis (proteostasis) mechanism is currently unclear. Here, we aimed identify molecular endoplasmic reticulum-associated degradation ClC-2, explore pathophysiological...

Loss-of-function mutations in the KV4.3 channel-encoding KCND3 gene are linked to neurodegenerative cerebellar ataxia. Patients suffering from neurodegeneration associated with iron deposition may also present The mechanism underlying brain accumulation remains unclear. Here, we aim ascertain potential pathogenic role of variant accumulation-related We presented a patient slowly progressive ataxia, parkinsonism, cognitive impairment, and basal ganglia cerebellum. Whole exome sequencing...

Abstract We have examined the expression of Thy‐1, an abundant glycosylphosphatidylinositol (GPI)‐anchored glycoprotein, in dorsal root ganglia (DRG) and associated nerve fascicles, during postnatal development following a crush. The levels Thy‐1 DRG neurons, roots, central processes spinal cord were rather low at day 2, gradually increased as neurons matured. During early development, within was equally distributed between plasma membrane cytosol. With maturation, staining intensities both...

Mutations in the human gene encoding neuron-specific Eag1 voltage-gated K+ channel are associated with neurodevelopmental diseases, indicating an important role of during brain development. A disease-causing mutation is linked to decreased protein stability that involves enhanced degradation by E3 ubiquitin ligase cullin 7 (CUL7). The general mechanisms governing homeostasis plasma membrane- and endoplasmic reticulum (ER)-localized channels, however, remain unclear. By using yeast two-hybrid...

Abstract Our previous study has shown that anti‐Thy‐1 antibody promotes neurite outgrowth of cultured dorsal root ganglion (DRG) neurons in a protein kinase A (PKA)‐dependent manner. The present provided another intracellular signaling pathway for the neurotrophic effect antibody. In DMSO‐treated control cells, Thy‐1 was enriched microdomain‐like structures on cell membranes by immunofluorescence observation. Treatment DRG with not only stimulated outgrowth, but also increased branching...

The assembly of four pore-forming α-subunits into tetramers is a prerequisite for the formation functional K(+) channels. A short carboxyl domain (CAD) in distal end cytoplasmic terminus has been implicated Eag α-subunits, subfamily ether-à-go-go channel family. precise role CAD tetrameric channels, however, remains unclear. Moreover, it not determined whether other protein regions also contribute to subunits. We addressed these questions by studying biophysical properties series different...

Whole exome sequencing (WES) has been used to detect rare causative variants in neurological diseases. However, the efficacy of WES genetic diagnosis clinically heterogeneous familial stroke remains inconclusive. We prospectively searched for disease-causing unrelated probands with defined by candidate gene/hotspot screening and/or WES, depending on subtypes and neuroimaging features at a referral center. The clinical significance each variant was determined according American College...

Abstract Thy‐1 is highly expressed in the mammalian nervous system. Our previous study showed that addition of anti‐Thy‐1 antibody to cultured dorsal root ganglionic (DRG) neurons promotes neurite outgrowth. In this study, we identified a novel signaling pathway mediating event. Treatment with function‐blocking antibodies enhanced outgrowth DRG terms total length, longest and branching points. To elucidate possible signal transduction involved, activation kinases was evaluated by Western...

Voltage-gated Ca V 2.1 channels comprise a pore-forming α 1A subunit with auxiliary 2 δ and β subunits. play an essential role in regulating synaptic signaling. Mutations the human gene encoding are associated cerebellar disease episodic ataxia type (EA2). Several EA2-causing mutants exhibit impaired protein stability exert dominant-negative suppression of wild-type (WT) expression via aberrant proteasomal degradation. Here, we set out to delineate degradation mechanism by identifying...

Mutations in the skeletal muscle-specific CLC-1 chloride channel are associated with human hereditary disease myotonia congenita. The molecular pathophysiology underlying some of disease-causing mutations can be ascribed to defective protein biosynthesis. folding is assisted by several chaperones and co-chaperones, including FK506-binding 8 (FKBP8). FKBP8 generally considered an endoplasmic reticulum- mitochondrion-resident membrane protein, but not thought contribute quality control at cell...

Eag1 is neuron-specific K(+) channel abundantly expressed in the brain and retina. Subcellular localization physiological analyses neurons reveal that may participate Ca(2+)-signaling processes synapse. Here, we searched for rat (rEag1)-binding proteins contribute to Ca(2+) regulation of channel. Yeast two-hybrid screening identified centrin 4, a member family Ca(2+)-binding proteins. GST pull-down immunoprecipitation assays retina lysates confirm interaction with rEag1 neurons. Centrin 4...

Abstract Loss-of-function mutations in the human gene encoding neuron-specific Ca 2+ channel V 2.1 are linked to neurological disease episodic ataxia type 2 (EA2), as well neurodevelopmental disorders such developmental delay and epileptic encephalopathy. Disease-associated mutants may exhibit defective proteostasis promote endoplasmic reticulum (ER)-associated degradation of their wild-type (WT) counterpart a dominant-negative manner. The E3 ubiquitin ligase RNF138 was previously shown...