Hongwon Kim

Electromagnetized gold nanoparticles mediate direct lineage reprogramming into induced dopamine neurons in vivo for Parkinson's disease therapy

Electromagnetic fields (EMF) are physical energy fields generated by electrically charged objects, and specific ranges of EMF can influence numerous biological processes, which include the control of cell fate and plasticity. In this study, we show that electromagnetized gold nanoparticles (AuNPs) in the presence of specific EMF conditions facilitate an efficient direct lineage reprogramming to induced dopamine neurons in vitro and in vivo. Remarkably, electromagnetic stimulation leads to a specific activation of the histone acetyltransferase Brd2, which results in histone H3K27 acetylation and a robust activation of neuron-specific genes. In vivo dopaminergic neuron reprogramming by EMF stimulation of AuNPs efficiently and non-invasively alleviated symptoms in mouse Parkinsons disease models. This study provides a proof of principle for EMF-based in vivo lineage conversion as a potentially viable and safe therapeutic strategy for the treatment of neurodegenerative disorders.

Generation of Integration-Free Induced Neurons Using Graphene Oxide-Polyethylenimine

Direct conversion of somatic cells into induced neurons (iNs) without inducing pluripotency has great therapeutic potential for treating central nervous system diseases. Reprogramming of somatic cells to iNs requires the introduction of several factors that drive cell-fate conversion, and viruses are commonly used to deliver these factors into somatic cells. However, novel gene-delivery systems that do not integrate transgenes into the genome are required to generate iNs for safe human clinical applications. In this study, it is investigated whether graphene oxide-polyethylenimine (GO-PEI) complexes are an efficient and safe system for messenger RNA delivery for direct reprogramming of iNs. The GO-PEI complexes show low cytotoxicity, high delivery efficiency, and directly converted fibroblasts into iNs without integrating factors into the genome. Moreover, in vivo transduction of reprogramming factors into the brain with GO-PEI complexes facilitates the production of iNs that alleviated Parkinsons disease symptoms in a mouse model. Thus, the GO-PEI delivery system may be used to safely obtain iNs and could be used to develop direct cell reprogramming-based therapies for neurodegenerative diseases.

Impaired motor coordination in Pitx3 overexpression mice

Midbrain dopaminergic (DA) neurons are involved in the regulation of voluntary movement and in emotion-related behaviors and are affected in Parkinsons disease (PD). The homeodomain transcription factor Pitx3, which is uniquely expressed in midbrain DA neurons, plays a critical role in the development, function and maintenance of midbrain DA neurons. Pitx3 deficiency results in selective deficits of midbrain DA neurons in the substantia nigra pars compacta (SNc), reminiscent of the specific DA neuronal loss observed in PD. In this study, we found that selective overexpression of Pitx3 in intact midbrain DA neurons significantly affects the function of midbrain DA neurons. We observed changes in DA levels and gene expressions in mice overexpressing Pitx3. Furthermore, motor coordination and locomotion activities are significantly affected in mice overexpressing Pitx3, suggesting that the expression level of Pitx3 plays an important role in the function of midbrain DA neuron in vivo.

Novel Neuroprotective Effects of Melanin-Concentrating Hormone in Parkinson’s Disease

Acupuncture has shown the therapeutic effect on various neurodegenerative disorders including Parkinson’s disease (PD). While investigating the neuroprotective mechanism of acupuncture, we firstly found the novel function of melanin-concentrating hormone (MCH) as a potent neuroprotective candidate. Here, we explored whether hypothalamic MCH mediates the neuroprotective action of acupuncture. In addition, we aimed at evaluating the neuroprotective effects of MCH and elucidating underlying mechanism in vitro and in vivo PD models. First, we tested whether hypothalamic MCH mediates the neuroprotective effects of acupuncture by challenging MCH-R1 antagonist (i.p.) in mice PD model. We also investigated whether MCH has a beneficial role in dopaminergic neuronal protection in vitro primary midbrain and human neuronal cultures and in vivo MPTP-induced, Pitx3−/−, and A53T mutant mice PD models. Transcriptomics followed by quantitative PCR and western blot analyses were performed to reveal the neuroprotective mechanism of MCH. We first found that hypothalamic MCH biosynthesis was directly activated by acupuncture treatment and that administration of an MCH-R1 antagonist reverses the neuroprotective effects of acupuncture. A novel finding is that MCH showed a beneficial role in dopaminergic neuron protection via downstream pathways related to neuronal survival. This is the first study to suggest the novel neuroprotective action of MCH as well as the involvement of hypothalamic MCH in the acupuncture effects in PD, which holds great promise for the application of MCH in the therapy of neurodegenerative diseases.

Modelling APOE ɛ3/4 allele-associated sporadic Alzheimer’s disease in an induced neuron

The recent generation of induced neurons by direct lineage conversion holds promise for in vitro modelling of sporadic Alzheimers disease. Here, we report the generation of induced neuron-based model of sporadic Alzheimers disease in mice and humans, and used this system to explore the pathogenic mechanisms resulting from the sporadic Alzheimers disease risk factor apolipoprotein E (APOE) ɛ3/4 allele. We show that mouse and human induced neurons overexpressing mutant amyloid precursor protein in the background of APOE ɛ3/4 allele exhibit altered amyloid precursor protein (APP) processing, abnormally increased production of amyloid-β42 and hyperphosphorylation of tau. Importantly, we demonstrate that APOE ɛ3/4 patient induced neuron culture models can faithfully recapitulate molecular signatures seen in APOE ɛ3/4-associated sporadic Alzheimers disease patients. Moreover, analysis of the gene network derived from APOE ɛ3/4 patient induced neurons reveals a strong interaction between APOE ɛ3/4 and another Alzheimers disease risk factor, desmoglein 2 (DSG2). Knockdown of DSG2 in APOE ɛ3/4 induced neurons effectively rescued defective APP processing, demonstrating the functional importance of this interaction. These data provide a direct connection between APOE ɛ3/4 and another Alzheimers disease susceptibility gene and demonstrate in proof of principle the utility of induced neuron-based modelling of Alzheimers disease for therapeutic discovery.

Salusin-β mediate neuroprotective effects for Parkinson's disease

Neuropeptides, small peptides found in many mammalian brain, play key roles in communicating with each other to modulate neuronal activity. Here, we reported that endogenous neuropeptide salusin-β has neuroprotective effects on the midbrain dopamine neurons and can be used as an effective therapeutic treatment for Parkinsons disease (PD). We found that the MrgprA1 receptor mediates the neuroprotective effects of salusin-β on the midbrain dopamine neurons. Importantly, intranasal administration of salusin-β in a PD mouse model show the neuroprotection of dopaminergic neurons and increased the survival of midbrain dopamine neurons. Furthermore, inhibition of the salusin-β receptor, MrgprA1, abolished the neuroprotective effects induced by salusin-β. Taken together, these results demonstrate the novel role of salusin-β in the central nervous system and salusin-β can be used as a novel therapeutic to effectively treat PD.

How much does depressive mood affect sleep for high school students

Background This research examined gender variations in depressive mood for high school students affected by emotional upset and how such depressive mood affect their sleep quality. Methods Research was conducted from September 2015 to October 2015. Both males and females were divided into normal group and depressive group by Zung Self-rating Depression Scale (ZSDS). Each group adopted the Pittsburgh Sleep Quality Index (PSQI) to measure sleep quality. Results Analysis was made on a total of 155 students, which were 83 male students and 72 female. The average ZSDS for all high school students was 43.38 and the average PSQI was 5.39. The number of male students in the normal and depressive group who were diagnosed with sleep disorder were 2 (3.8%) and 9 (29.0%), respectively ( P P P Conclusion This research showed that sleep quality of all high school students was not too bad but it can be problematic for those with depressive mood. Especially, female students were diagnosed with sleep disorder more than male students.

P01-188 - Regional brain perfusion differences associated with norepinephrine transporter gene polymorphisms in ADHD

Objectives The aim of this study was to examine whether the presence of risk alleles of the norepinephrine transporter gene (SLC6A2) polymorphisms is associated with differences in regional cerebral blood flow (rCBF) measured by 99m Tc-HMPAO single photon emission computerized tomography in a Korean sample of ADHD. Methods The present study included 24 children with ADHD (9.5±2.4 years), consisting of 20 boys and 4 girls, aged 6-16 years. We investigated the G1287A and -3081(A/T) polymorphisms of the SLC6A2. The rCBF was compared between the ADHD subjects with and without risk alleles at the G1287A polymorphism and at the -3081(A/T) polymorphism. Image analyses were performed with voxelwise t -statistics using SPM2. Results 1) The ADHD subjects with the A allele (risk allele) at the G1287A polymorphism showed reduced perfusion in the left middle frontal gyrus, left inferior parietal lobule, precuneus, right superior frontal gyrus, and right superior parietal lobule as compared with ADHD subjects without the A allele (p 2) The ADHD subjects with the A allele at the G1287A polymorphism showed increased perfusion in the right middle frontal gyrus, right middle temporal gyrus, right superior temporal gyrus, right fusiform gyrus, right precentral gyrus, and right anterior lobe of cerebellum as compared with ADHD subjects without the A allele (p 3) No significant perfusion differences were found between ADHD subjects with and without the T allele (risk allele) at the -3081(A/T) polymorphism. Conclusion Our findings suggest that the SLC6A2 G1287A polymorphism might exert differential effects on rCBF in children with ADHD.