Genetic and clinical landscape of Chinese frontotemporal dementia: dominance of TBK1 and OPTN mutations.

Background: Our study aims to evaluate the genetic and phenotypic spectrum of Frontotemporal dementia (FTD) gene variant carriers in Chinese populations, investigate mutation frequencies, and assess the functional properties of TBK1 and OPTN variants.

Methods: Clinically diagnosed FTD patients underwent genetic analysis through exome sequencing, repeat-primed polymerase chain reaction, and Sanger sequencing. TBK1 and OPTN variants were biologically characterized in vitro using immunofluorescence, immunoprecipitation, and immunoblotting analysis.

A light-controlled phospholipase C for imaging of lipid dynamics and controlling neural plasticity.

Phospholipase C (PLC) is a key enzyme that regulates physiological processes via lipid and calcium signaling. Despite advances in protein engineering, no tools are available for direct PLC control. Here, we developed a novel optogenetic tool, light-controlled PLCβ (opto-PLCβ).

All-optical presynaptic plasticity induction by photoactivated adenylyl cyclase targeted to axon terminals.

Intracellular signaling plays essential roles in various cell types. In the central nervous system, signaling cascades are strictly regulated in a spatiotemporally specific manner to govern brain function; for example, presynaptic cyclic adenosine monophosphate (cAMP) can enhance the probability of neurotransmitter release. In the last decade, channelrhodopsin-2 has been engineered for subcellular targeting using localization tags, but optogenetic tools for intracellular signaling are not well developed.

Case report: Reversible brain atrophy with low titer anti-amphiphysin antibodies related to gastric adenocarcinoma.

Amphiphysin (AMPH) autoimmunity is associated with a variety of neurological complications, including encephalitis, peripheral neuropathy, myelopathy, and cerebellar syndrome. Its diagnosis is based on clinical neurological deficits and the presence of serum anti-AMPH antibodies. Active immunotherapy, such as intravenous immunoglobulins, steroids, and other immunosuppressive therapies, has been reported to be effective in most patients.

Experience-dependent changes in affective valence of taste in male mice.

Taste plays an essential role in the evaluation of food quality by detecting potential harm and benefit in what animals are about to eat and drink. While the affective valence of taste signals is supposed to be innately determined, taste preference can also be drastically modified by previous taste experiences of the animals. However, how the experience-dependent taste preference is developed and the neuronal mechanisms involved in this process are poorly understood.

A novel technique for large-fragment knock-in animal production without ex vivo handling of zygotes.

CRISPR/Cas-based genome editing has dramatically improved genetic modification technology. In situ electroporation called genome editing via oviductal nucleic acid delivery (GONAD), which eliminates the need for ex vivo embryo handling, is technically the simplest method for gene transfer and can be performed in laboratories without developmental engineering expertise including micromanipulation techniques. However, the use of this method remains challenging in the case of large-fragment knock-in, such as gene expression cassettes.

Post-developmental plasticity of the primary rod pathway allows restoration of visually guided behaviors.

The formation of neural circuits occurs in a programmed fashion, but proper activity in the circuit is essential for refining the organization necessary for driving complex behavioral tasks. In the retina, sensory deprivation during the critical period of development is well known to perturb the organization of the visual circuit making the animals unable to use vision for behavior. However, the extent of plasticity, molecular factors involved, and malleability of individual channels in the circuit to manipulations outside of the critical period are not well understood.

Ubap1 knock-in mice reproduced the phenotype of SPG80.

SPG80 is a neurodegenerative disorder characterized by a pure type of juvenile-onset hereditary spastic paraplegia and is caused by a heterozygous mutation of the UBAP1 (ubiquitin-associated protein 1) gene. UBAP1 is one of the subunits of the endosomal sorting complex required for transport I and plays a role in endosome sorting by binding to ubiquitin-tagged proteins. In this study, we generated novel Ubap1 knock-in mice, in which the SOUBA domain of Ubap1 was completely deleted with the UMA domain being intact, as an animal model of SPG80.

Novel Variation in Female Carriers With Intellectual Disability and Atypical Parkinsonism.

Background And Objectives: Variations in cause the X-linked neurologic disorder Christianson syndrome in males. Meanwhile, female carriers with variations may remain asymptomatic or develop intellectual disability, behavioral problems, and psychiatric illnesses. Only a few female carriers have been reported to have associated atypical parkinsonism in late life.

Planar cell polarity protein Vangl2 and its interacting protein Ap2m1 regulate dendritic branching in cortical neurons.

Van Gogh-like 2 (Vangl2) is a mammalian homolog of Drosophila core planar cell polarity (PCP) protein Vang/Strabismus, which organizes asymmetric cell axes for developmental proliferation, fate determination, and polarized movements in multiple tissues, including neurons. Although the PCP pathway has an essential role for dendrite and dendritic spine formation, the molecular mechanism remains to be clarified. To investigate the mechanism of Vangl2-related neuronal development, we screened for proteins that interact with the Vangl2 cytosolic N-terminus from postnatal day 9 mouse brains using a yeast two-hybrid system.

A Novel Heterozygous Missense Variant in the CIAO1 Gene in a Family with Alzheimer's Disease: The Val67Ile Variant Promotes the Interaction of CIAO1 and Amyloid-β Protein Precursor.

Familial dementia is a rare inherited disease involving progressive impairment of memory, thinking, and behavior. We report a novel heterozygous pathogenic variant (c.199G > A, p.

An engineered channelrhodopsin optimized for axon terminal activation and circuit mapping.

Optogenetic tools such as channelrhodopsin-2 (ChR2) enable the manipulation and mapping of neural circuits. However, ChR2 variants selectively transported down a neuron's long-range axonal projections for precise presynaptic activation remain lacking. As a result, ChR2 activation is often contaminated by the spurious activation of en passant fibers that compromise the accurate interpretation of functional effects.

RFC1 repeat expansion in Japanese patients with late-onset cerebellar ataxia.

Recently, the expansion of an intronic AAGGG repeat in the replication factor C subunit 1 (RFC1) gene was reported to cause cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). In Europeans, the expansion accounted for 22% of sporadic patients with late-onset ataxia. We genotyped 37 Japanese patients comprising 25 familial (autosomal recessive or undecided transmission) and 12 sporadic ones with late-onset ataxia.

Prickle2 and Igsf9b Coordinately Regulate the Cytoarchitecture of the Axon Initial Segment.

Prickle2 has been identified in genetic studies of subjects with autism spectrum disorder (ASD) and epilepsy, but the pathological mechanism of Prickle2 remains to be fully understood. Proteomic analysis of Prickle2 with mass spectrometry revealed twenty-eight Prickle2 interactors, including immunoglobulin superfamily member 9b (Igsf9b), in the brain. Here, because Igsf9 family proteins are associated with psychiatric diseases and seizures, we studied the physiological interaction between Prickle2 and Igsf9b.

Development of an L-type Ca channel-dependent Ca transient during the radial migration of cortical excitatory neurons.

Increasing evidence has shown that voltage-gated L-type Ca channels (LTCCs) are crucial for neurodevelopmental events, including neuronal differentiation/migration and neurite morphogenesis/extension. However, the time course of their functional maturation during the development of excitatory neurons remains unknown. Using a combination of fluorescence in situ hybridization and in utero electroporation-based labeling, we found that the transcripts of Cacna1c and Cacna1d, which encode the LTCC pore-forming subunits, were upregulated in the intermediate zone (IZ) during radial migration.

Neuron-enriched phosphatase and actin regulator 3 (Phactr3)/ nuclear scaffold-associated PP1-inhibiting protein (Scapinin) regulates dendritic morphology via its protein phosphatase 1-binding domain.

Phosphatase and actin regulator 3/nuclear scaffold-associated protein phosphatase 1-inhibiting protein (Phactr3/Scapinin) is an actin- and protein phosphatase 1 (PP1)-binding protein known to negatively regulate axon elongation. In this study, we examined the expression pattern of Phactr3/Scapinin in several tissues and investigated the effect of Phactr3/Scapinin on dendritic morphology of cortical neurons. Results showed that Phactr3/Scapinin expression was up-regulated in the developing brain and enriched in neurons and in the postsynaptic density fraction, but not in astrocytes.

Presynaptic development is controlled by the core active zone proteins CAST/ELKS.

Key Points: CAST/ELKS are positive regulators of presynaptic growth and are suppressors of active zone expansion at the developing mouse calyx of Held. CAST/ELKS regulate all three Ca 2 subtype channel levels in the presynaptic terminal and not just Ca 2.1.

Impaired experience-dependent maternal care in presynaptic active zone protein CAST-deficient dams.

Although sociological studies affirm the importance of parental care in the survival of offspring, maltreatment-including child neglect-remains prevalent in many countries. While child neglect is well known to affect child development, the causes of maternal neglect are poorly understood. Here, we found that female mice with a deletion mutation of CAST (a presynaptic release-machinery protein) showed significantly reduced weaning rate when primiparous and a recovered rate when multiparous.

Double deletion of the active zone proteins CAST/ELKS in the mouse forebrain causes high mortality of newborn pups.

Presynaptic active zone cytomatrix proteins are essential elements of neurotransmitter release machinery that govern neural transmission. Among active zone proteins, cytomatrix at the active zone-associated structural protein (CAST) is known to regulate active zone size in retinal photoreceptors and neurotransmitter release by recruiting Ca channels at various synapses. However, the role of ELKS-a protein from the same family as CAST-and the synergistic roles of CAST/ELKS have not been thoroughly investigated, particularly with regard to mouse behavior.

VPS13D-related disorders presenting as a pure and complicated form of hereditary spastic paraplegia.

Background: Alterations of vacuolar protein sorting-associated protein 13 (VPS13) family members including VPS13A, VPS13B, and VPS13C lead to chorea acanthocytosis, Cohen syndrome, and parkinsonism, respectively. Recently, VPS13D mutations were identified as a cause of VPS13D-related movement disorders, which show several phenotypes including chorea, dystonia, spastic ataxia, and spastic paraplegia.

Methods: We applied whole-exome analysis for a patient with a complicated form of hereditary spastic paraplegia (HSP) and her unaffected parents.

UBAP1 mutations cause juvenile-onset hereditary spastic paraplegias (SPG80) and impair UBAP1 targeting to endosomes.

We aimed to find a new causative gene and elucidate the molecular mechanisms underlying a new type of hereditary spastic paraplegia (HSP). Patients with HSP were recruited from the Japan Spastic Paraplegia Research Consortium (JASPAC). Exome sequencing of genomic DNA from patients in four families was carried out, followed by Sanger sequencing of the UBAP1 gene.

Role of the active zone protein, ELKS, in insulin secretion from pancreatic β-cells.

Background: Insulin is stored within large dense-core granules in pancreatic beta (β)-cells and is released by Ca-triggered exocytosis with increasing blood glucose levels. Polarized and targeted secretion of insulin from β-cells in pancreatic islets into the vasculature has been proposed; however, the mechanisms related to cellular and molecular localization remain largely unknown. Within nerve terminals, the Ca-dependent release of a polarized transmitter is limited to the active zone, a highly specialized area of the presynaptic membrane.

Vangl2 interaction plays a role in the proteasomal degradation of Prickle2.

The PET and LIM domain-containing protein, Prickle, plays a key role in planar cell polarity (PCP) in Drosophila. It has been reported that mutations in the PRICKLE2 gene, which encodes one of the human orthologues of Prickle, are associated with human diseases such as epilepsy and autism spectrum disorder. To develop preventive and therapeutic strategies for these intractable diseases, we studied the regulation of Prickle2 protein levels in transfected HEK293T cells.