BackgroundHuntington’s disease (HD) is an incurable hereditary neurodegenerative disorder, which manifests itself as a loss of GABAergic medium spiny (GABA MS) neurons in the striatum and caused by an expansion of the CAG repeat in exon 1 of the huntingtin gene. There is no cure for HD, existing pharmaceutical can only relieve its symptoms.ResultsHere, induced pluripotent stem cells were established from patients with low CAG repeat expansion in the huntingtin gene, and were then efficiently differentiated into GABA MS-like neurons (GMSLNs) under defined culture conditions. The generated HD GMSLNs recapitulated disease pathology in vitro, as evidenced by mutant huntingtin protein aggregation, increased number of lysosomes/autophagosomes, nuclear indentations, and enhanced neuronal death during cell aging. Moreover, store-operated channel (SOC) currents were detected in the differentiated neurons, and enhanced calcium entry was reproducibly demonstrated in all HD GMSLNs genotypes. Additionally, the quinazoline derivative, EVP4593, reduced the number of lysosomes/autophagosomes and SOC currents in HD GMSLNs and exerted neuroprotective effects during cell aging.ConclusionsOur data is the first to demonstrate the direct link of nuclear morphology and SOC calcium deregulation to mutant huntingtin protein expression in iPSCs-derived neurons with disease-mimetic hallmarks, providing a valuable tool for identification of candidate anti-HD drugs. Our experiments demonstrated that EVP4593 may be a promising anti-HD drug.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0092-5) contains supplementary material, which is available to authorized users.

c Peptidoglycan recognition proteins (PGLYRPs) are innate immune components that recognize the peptidoglycan and lipopolysaccharides of bacteria and exhibit antibacterial activity. Recently, the obligate intracellular parasite Chlamydia trachomatis was shown to have peptidoglycan. However, the antichlamydial activity of PGLYRPs has not yet been demonstrated. The aim of our study was to test whether PGLYRPs exhibit antibacterial activity against C. trachomatis. Thus, we cloned the regions containing the human Pglyrp1, Pglyrp2, Pglyrp3, and Pglyrp4 genes for subsequent expression in human cell lines. We obtained stable HeLa cell lines that secrete recombinant human PGLYRPs into culture medium. We also generated purified recombinant PGLYRP1, -2, and -4 and confirmed their activities against Gram-positive (Bacillus subtilis) and Gram-negative (Escherichia coli) bacteria. Furthermore, we examined the activities of recombinant PGLYRPs against C. trachomatis and determined their MICs. We also observed a decrease in the infectious ability of chlamydial elementary bodies in the next generation after a single exposure to PGLYRPs. Finally, we demonstrated that PGLYRPs attach to C. trachomatis elementary bodies and activate the expression of the chlamydial two-component stress response system. Thus, PGLYRPs inhibit the development of chlamydial infection. P eptidoglycan recognition proteins (PGLYRPs) are members of the innate immune system. Initially, they were shown to bind bacterial peptidoglycan and activate the prophenoloxidase pathway in insects (1). Later, PGLYRPs were also found in mammals and other taxonomic groups (2, 3). Mammals have four PGLYRPs, PGLYRP1 to -4, that have been identified as bactericidal proteins (4, 5). PGLYRPs have been shown to recognize not only bacterial peptidoglycan but also lipopolysaccharides in the outer membrane of Gram-negative bacteria (6). In 2010, a novel bacterial killing mechanism that involves PGLYRPs was suggested. PGLYRPs bind to bacterial cell wall peptidoglycan or outer membrane lipopolysaccharides and hyperactivate a stress defense response in bacteria that leads to bacterial suicide (7). PGLYRPs were shown to bind peptidoglycan and lipopolysaccharides in Bacillus subtilis and Escherichia coli, respectively, and activate the bacterial two-component systems (TCSs) CssS-CssR in B. subtilis and CpxA-CpxR in E. coli, resulting in bacterial death (7). In these TCSs, CssS and CpxA include a histidine kinase (HK) domain and CssR and CpxR act as response regulators. In early studies, Lu et al. (8) demonstrated the bactericidal activity of PGLYRPs against different Gram-positive and Gram-negative bacteria in vitro and in vivo. PGLYRPs exhibit both recognition and effector activities against different bacteria (3, 5, 7-9). However, their activity against intracellular pathogenic parasites such as chlamydiae has not yet been demonstrated.Chlamydiae alternate between two forms: the infectious, metabolically inactive elementary body (EB) and the noninfectious, metabolically active reticu...

As essential conservative component of the innate immune systems of living organisms, antimicrobial peptides (AMPs) could complement pharmaceuticals that increasingly fail to combat various pathogens exhibiting increased resistance to microbial antibiotics. Among the properties of AMPs that suggest their potential as therapeutic agents, diverse peptides in the venoms of various predators demonstrate antimicrobial activity and kill a wide range of microorganisms. To identify potent AMPs, the study reported here involved a transcriptomic profiling of the tentacle secretion of the sea anemone Cnidopus japonicus. An in silico search algorithm designed to discover toxin-like proteins containing AMPs was developed based on the evaluation of the properties and structural peculiarities of amino acid sequences. The algorithm revealed new proteins of the anemone containing antimicrobial candidate sequences, and 10 AMPs verified using high-throughput proteomics were synthesized. The antimicrobial activity of the candidate molecules was experimentally estimated against Gram-positive and -negative bacteria. Ultimately, three peptides exhibited antimicrobial activity against bacterial strains, which suggests that the method can be applied to reveal new AMPs in the venoms of other predators as well.

No abstract

No abstract