Journal of neurogenetics最新文献

Neurogenetic research using the Drosophila model has immensely expanded around the world. Likewise, scientists in South Korea have leveraged the advantages of Drosophila genetic tools to understand various neurobiological processes. In this special issue, we will overview the history of Drosophila neurogenetic research in South Korea that led to significant discoveries and notably implications. We will describe how Drosophila system was first introduced to elevate neural developmental studies in 1990s. Establishing Drosophila-related resources has been a key venture, which led to the generation of over 100,000 mutant lines and the launch of the K-Gut initiative with Korea Drosophila Research Center (KDRC). These resources have supported the pioneer studies in modeling human disease and understanding genes and neural circuits that regulate animal behavior and physiology.

Tau is a microtubule-associated protein that forms insoluble filaments that accumulate as neurofibrillary tangles in neurodegenerative diseases such as Alzheimer's disease and other related tauopathies. A relationship between abnormal Tau accumulation and ubiquitin-proteasome system impairment has been reported. However, the molecular mechanism linking Tau accumulation and ubiquitin proteasome system (UPS) dysfunction remains unclear. Here, we show that overexpression of wild-type or mutant (P301L) Tau increases the abundance of polyubiquitinated proteins and activates the autophagy-lysosome pathway in mammalian neuronal cells. Previous studies found that PTK2 inhibition mitigates toxicity induced by UPS impairment. Thus, we investigated whether PTK2 inhibition can attenuate Tau-induced UPS impairment and cell toxicity. We found that PTK2 inhibition significantly reduces Tau-induced death in mammalian neuronal cells. Moreover, overexpression of WT or mutant Tau increased the phosphorylation levels of PTK2 and p62. We also confirmed that PTK2 inhibition suppresses Tau-induced phosphorylation of PTK2 and p62. Furthermore, PTK2 inhibition significantly attenuated the climbing defect and shortened the lifespan in the Drosophila model of tauopathy. In addition, we observed that phosphorylation of p62 is markedly increased in Alzheimer's disease patients with tauopathies. Taken together, our results indicate that the UPS dysfunction induced by Tau accumulation might contribute directly to neurodegeneration in tauopathies and that PTK2 could be a promising therapeutic target for tauopathies.

Animals are able to detect the nutritional content of sugar independently of taste. When given a choice between nutritive sugar and nonnutritive sugar, animals develop a preference for nutritive sugar over nonnutritive sugar during a period of food deprivation (Buchanan et al., 2022; Dus et al., 2011; 2015; Tan et al., 2020; Tellez et al., 2016). To quantify behavioral features during an episode of licking nutritive versus nonnutritive sugar, we implemented a multi-vision, deep learning-based 3D pose estimation system, termed the AI Vision Analysis for Three-dimensional Action in Real-Time (AVATAR)(Kim et al., 2022). Using this method, we found that mice exhibit significantly different approach behavioral responses toward nutritive sugar versus nonnutritive sugar even before licking a sugar solution. Notably, the behavioral sequences during the approach toward nutritive versus nonnutritive sugar became significantly different over time. These results suggest that the nutritional value of sugar not only promotes its consumption but also elicits distinct repertoires of feeding behavior in deprived mice.

The brain plays an essential role in regulating physiological homeostasis by communicating with other organs. Neuronal cells either directly innervate target tissues and transmit signals or secrete systemic factors into the hemolymph to regulate bodily functions, including physiology, development, metabolism, and immunity. In this review, we discuss the systemic functions of inter-organ communication mediated by the brain in four distinct categories: (1) nutrient sensing and feeding, (2) gastrointestinal activity and metabolism, (3) development and metamorphosis, and (4) immunity and hematopoiesis. First, we describe how chemosensory signals are sensed and transmitted to the brain in Drosophila and how the brain stimulates or modifies feeding behavior. Second, we summarize the brain-organ axis that regulates appetite activities and neuroendocrine pathways that maintain metabolic homeostasis. Third, we discuss how overall development in Drosophila is achieved by insulin and how it affects ecdysone signaling to initiate pupariation. Finally, we discuss how the central or peripheral nervous system controls hematopoiesis and innate immunity in Drosophila larvae. Given the functional parallels between Drosophila and humans, homologous pathways are likely to be conserved in human development and disease models, and the fly model system will continue to provide mechanistic insights into understanding complex interactions.

Circadian rhythms and sleep homeostasis constitute the two-process model for daily sleep regulation. However, evidence for circadian control of sleep-wake cycles has been relatively short since clock-less animals often show sleep behaviors quantitatively comparable to wild-type. Here we examine Drosophila sleep behaviors under different light-dark regimes and demonstrate that circadian clocks gate light-induced arousal. Genetic excitation of tyrosine decarboxylase 2 (TDC2)-expressing neurons suppressed sleep more evidently at night, causing nocturnal activity. The arousal effects were likely mediated in part by glutamate transmission from the octopaminergic neurons and substantially masked by light. Application of T12 cycles (6-h light: 6-h dark) further showed that the light-sensitive effects of TDC2 neurons depended on the time of the day. In particular, light-sensing via visual input pathway led to strong sleep suppression at subjective night, and such an effect disappeared in clock-less mutants. Transgenic mapping revealed that light-induced arousal and free-running behavioral rhythms require distinct groups of circadian pacemaker neurons. These results provide convincing evidence that circadian control of sleep is mediated by the dedicated clock neurons for light-induced arousal.

Telomerase is reactivated in the majority of cancers. For instance, in gliomas, it is common that the TERT promoter is mutated. Research on telomere promoter GC islands have been focused primarily on proximal TERT promoter but little is known about the distal promoter. Therefore, in this study, we investigated the proximal and distal TERT promoter, in terms of DNA methylation. We did bisulfite sequencing in zebrafish tissue samples for the distal tert promoter. In the zebrafish brain tissues, we identified a hypomethylation site in the tert promoter, and found that this hypomethylation was associated with aging and shortened telomeres. Through site directed mutagenesis in glioma cell lines, we changed 10 GC spots individually, cloned into a reporter vector, and measured promoter activity. Finally, we silenced DNMT3B and measured telomerase activity along with vidaza and adriamycin treatments. Site directed mutagenesis of glioma cell lines revealed that each of the 10 GC spots are critical for telomerase activity. Changing GC to AT abolished promoter activity in all spots when transfected into glioma cell lines. Then, through silencing of DNMT3B, we observed a reduction in hTERT expression levels, while hTR remained the same, and a major increase in senescence-associated beta-galactosidase activity. Finally, we propose a model regarding the efficacy of two chemotherapeutic drugs, adriamycin and azacytidine, on gliomas. Here, we show that distal TERT promoter is critical; changing even one GC to AT abolishes TERT promoter activity. DNMT3B, a de novo methyltransferase, together with GC islands in distal TERT promoter plays an important role in regulation of telomerase expression and senescence.

Global developmental delay (GDD) is a lifelong disability that affects 1-3% of the population around the globe. It is phenotypically variable and highly heterogeneous in terms of the underlying genetics. Patients with GDD are intellectually disabled (ID) manifesting cognitive impairment and deficient adaptive behavior. Here, we investigated a two-looped consanguineous family segregating severe ID, seizure, and progressive microcephaly. Magnetic resonance imaging (MRI) of the brain showed mild brain atrophy and myelination defect. Whole exome sequencing (WES) was performed on the DNA samples of two patients and a novel homozygous missense variant (Chr11:g0.93528085; NM_004268.5_c.871T > C; p. Trp291Gly) was identified in the MED17 gene. Sanger sequencing revealed that the identified variant is heterozygous in both parents and healthy siblings. This variant is conserved among different species, causes a non-conserved amino acid change, and is predicted deleterious by various in silico tools. The variant is not reported in population variant databases. MED17 (OMIM: 613668) encodes for the mediator of RNA polymerase II transcription complex subunit 17. Structure modeling of MED17 protein revealed that Trp291 is involved in different inter-helical interactions, providing structural stability. Replacement of Trp291Gly, a less hydrophobic amino acid loses the inter-helical interaction leading to a perturb variant of MED17 protein.

Alterations to the LRRK2 gene have been associated with Parkinson's disease and alcohol consumption in animals and humans. Furthermore, these disorders are strongly related to anxiety disorders (ADs). Thus, we investigated how the LRRK2 gene might influence anxiety in humans and mice. We elaborated a systematic review based on the PRISMA Statement of studies that investigated levels of anxiety in animal or human models with alterations in the LRRK2 gene. The search was conducted in the PubMed, Scopus, and Web of Science databases, and in reference lists with descriptors related to ADs and the LRRK2. From the 62 articles assessed for eligibility, 16 were included: 11 conducted in humans and seven, in mice. Lrrk2 KO mice and the LRRK2 G2019S, LRRK2 R1441G, and LRRK2 R1441C variants were addressed. Five articles reported an increase in anxiety levels concerning the LRRK2 variants. Decreased anxiety levels were observed in two articles, one focusing on the LRRK2 G2019S and the other, on the Lrrk2 KO mice. Eight other articles reported no differences in anxiety levels in individuals with Lrrk2 alterations compared to their healthy controls. This study discusses a possible influence between the LRRK2 gene and anxiety, adding information to the existing knowledge respecting the influence of genetics on anxiety.

Pleckstrin homology like domain family A member 2 (PHLDA2) is an imprinted gene expressed in placenta and has been shown to be associated with tumor progression. However, the effect of PHLDA2 on glioma cell growth has not been reported yet. Data based on TCGA database showed that PHLDA2 was up-regulated in glioma tissues. Moreover, PHLDA2 was also elevated in glioma cells. Functional assays showed that siRNA-mediated knockdown of PHLDA2 reduced cell viability of glioma cells and suppressed the cell proliferation. Cell apoptosis of glioma cells was promoted by silencing of PHLDA2 with increased Bax and decreased Bcl-2. Silencing of PHLDA2 reduced protein expression of p62, enhanced LC3 and Beclin1 to promote autophagy. Phosphorylated AKT and mTOR were down-regulated in glioma cells by interference of PHLDA2. In conclusion, downregulation of PHLDA2 inhibited glioma cell proliferation, and promoted cell apoptosis and autophagy through inactivation of AKT/mTOR signaling.