Generation of a human iPSC line from a Parkinson's disease patient with a novel CHCHD2 mutation (p.R145Q).

Mutations in CHCHD2 have been reported to be associated with familial Parkinson's disease (PD). We generated a human induced pluripotent stem cell (hiPSC) line by reprogramming dermal fibroblasts from a PD patient harboring a novel CHCHD2 mutation (c.434G > A, p.

Multicomponent metal-organic framework nanocomposites for tumor-responsive synergistic therapy.

Targeted tumor therapy through tumor microenvironment (TME)-responsive nanoplatforms is an emerging treatment strategy used to enhance tumor-specificity to selectively kill cancer cells. Here, we introduce a nanosized zeolitic imidazolate framework-8 (ZIF-8) that simultaneously contains natural glucose oxidase (GOx) and Prussian blue nanoparticles (PBNPs) to construct multi-component metal-organic framework nanocomposites (denoted as ZIF@GOx@PBNPs), which possess cascade catalytic activity selectively within the TME. Once reaching a tumor site, GOx and PBNPs inside the nanocomposites are sequentially released and participate in the cascade catalytic reaction.

Spotting-based differentiation of functional dopaminergic progenitors from human pluripotent stem cells.

To fully realize the potential of human pluripotent stem cells (hPSCs) for both therapeutic and research purposes, it is critical to follow an efficient and reliable in vitro differentiation method that is based on optimal physical, chemical and developmental cues. This highly reproducible protocol describes how to grow hPSCs such as human induced pluripotent and embryonic stem cells in a physically confined area ('spot') and efficiently differentiate them into a highly enriched population of healthy and functional midbrain dopamine progenitors (mDAPs) and midbrain dopamine neurons (mDANs). The protocol takes 28 d, during which cells first grow and differentiate in spots for 14 d and then are replated and further differentiated for a further 14 d as a monolayer culture.

Analysis of multi-omics data on the relationship between epigenetic changes and nervous system disorders caused by exposure to environmentally harmful substances.

Environmentally hazardous substances and exposure to these can cause various diseases. Volatile organic compounds can easily evaporate into the atmosphere, thereby exerting toxic effects through either the skin or respiratory tract exposures. Toluene, a neurotoxin, has been widely used in various industries.

Matrix Metalloproteinase-8 Inhibitor Ameliorates Inflammatory Responses and Behavioral Deficits in LRRK2 G2019S Parkinson's Disease Model Mice.

Parkinson's disease (PD) is a neurodegenerative disorder that involves the loss of dopaminergic neurons in the substantia nigra (SN). Matrix metalloproteinases-8 (MMP-8), neutrophil collagenase, is a functional player in the progressive pathology of various inflammatory disorders. In this study, we administered an MMP-8 inhibitor (MMP-8i) in Leucine-rich repeat kinase 2 (LRRK2) G2019S transgenic mice, to determine the effects of MMP-8i on PD pathology.

Brain cells derived from Alzheimer's disease patients have multiple specific innate abnormalities in energy metabolism.

Altered energy metabolism has been implicated both in aging and the pathogenesis of late-onset Alzheimer's disease (LOAD). However, it is unclear which anomalies are acquired phenotypes and which are inherent and predispose to disease. We report that neural progenitor cells and astrocytes differentiated from LOAD patient-derived induced pluripotent stem cells exhibit multiple inter-related bioenergetic alterations including: changes in energy production by mitochondrial respiration versus glycolysis, as a consequence of alterations in bioenergetic substrate processing and transfer of reducing agents, reduced levels of NAD/NADH, diminished glucose uptake and response rates to insulin (INS)/IGF-1 signaling, decreased INS receptor and glucose transporter 1 densities, and changes in the metabolic transcriptome.

Modulation of SETDB1 activity by APQ ameliorates heterochromatin condensation, motor function, and neuropathology in a Huntington's disease mouse model.

The present study describes evaluation of epigenetic regulation by a small molecule as the therapeutic potential for treatment of Huntington's disease (HD). We identified 5-allyloxy-2-(pyrrolidin-1-yl)quinoline (APQ) as a novel SETDB1/ESET inhibitor using a combined and cell based screening system. APQ reduced SETDB1 activity and H3K9me3 levels in a HD cell line model.

Iroquois Homeobox Protein 2 Identified as a Potential Biomarker for Parkinson's Disease.

The diagnosis of Parkinson's disease (PD) is initiated after the occurrence of motor symptoms, such as resting tremors, rigidity, and bradykinesia. According to previous reports, non-motor symptoms, notably gastrointestinal dysfunction, could potentially be early biomarkers in PD patients as such symptoms occur earlier than motor symptoms. However, connecting PD to the intestine is methodologically challenging.

Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson's Disease.

We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in a patient with idiopathic Parkinson's disease. The patient-specific progenitor cells were produced under Good Manufacturing Practice conditions and characterized as having the phenotypic properties of substantia nigra pars compacta neurons; testing in a humanized mouse model (involving peripheral-blood mononuclear cells) indicated an absence of immunogenicity to these cells. The cells were implanted into the putamen (left hemisphere followed by right hemisphere, 6 months apart) of a patient with Parkinson's disease, without the need for immunosuppression.

Human autologous iPSC-derived dopaminergic progenitors restore motor function in Parkinson's disease models.

Parkinson's disease (PD) is a neurodegenerative disorder associated with loss of striatal dopamine, secondary to degeneration of midbrain dopamine (mDA) neurons in the substantia nigra, rendering cell transplantation a promising therapeutic strategy. To establish human induced pluripotent stem cell-based (hiPSC-based) autologous cell therapy, we report a platform of core techniques for the production of mDA progenitors as a safe and effective therapeutic product. First, by combining metabolism-regulating microRNAs with reprogramming factors, we developed a method to more efficiently generate clinical-grade iPSCs, as evidenced by genomic integrity and unbiased pluripotent potential.

HDAC Inhibition by Valproic Acid Induces Neuroprotection and Improvement of PD-like Behaviors in LRRK2 R1441G Transgenic Mice.

Parkinson's disease (PD) is one of the late-onset neurodegenerative movement disorder. Major pathological markers of PD include progressive loss of dopaminergic neurons, Lewy body formation, genetic mutations, and environmental factors. Epigenetic regulation of specific gene expression via impaired histone acetylation is associated with neuronal dysfunction in various neurodegenerative diseases.

Oxidized DJ-1 Levels in Urine Samples as a Putative Biomarker for Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Oxidative stress is the most critical risk factor for neurodegenerative diseases, including Alzheimer's disease (AD) and Huntington's disease (HD). Numerous reports have demonstrated that oxidative stress aggravates cytotoxicity in dopaminergic neurons and accelerates the formation of protein inclusions.

Age-associated bimodal transcriptional drift reduces intergenic disparities in transcription.

This study addressed the question of how well the quantitative transcriptome structure established in early life is maintained and how consistently it appears with increasing age, and if there is age-associated alteration of gene expression (AGE), how much influence the Huntington's disease (HD) genotype exerts on it. We examined 285 exonic sequences of 175 genes using targeted PCR sequencing in skeletal muscle, brain, and splenic CD4+ T cells of wild-type and HD mice. In contrast to the muscle and brain, T cells exhibited large AGE, suggesting a strong contribution to functional decline of the organism.

Suppression of neuroinflammation by matrix metalloproteinase-8 inhibitor in aged normal and LRRK2 G2019S Parkinson's disease model mice challenged with lipopolysaccharide.

Microglial priming is caused by aging and neurodegenerative diseases, and is characterized by an exaggerated microglial inflammatory response to secondary and sub-threshold challenges. In the present study, we examined the effects of the matrix metalloproteinase-8 (MMP-8) inhibitor (M8I) on the brain of aged normal and leucine-rich repeat kinase 2 (LRRK2) G2019S Parkinson's disease (PD) model mice systemically stimulated with lipopolysaccharide (LPS). The results indicated that Iba-1 positive microglia and GFAP-positive astrocytes, which were increased by LPS, significantly decreased by M8I in aged normal and PD model mice.

Age-associated chromatin relaxation is enhanced in Huntington's disease mice.

Expansion of polyglutamine stretch in the huntingtin (HTT) protein is a major cause of Huntington's disease (HD). The polyglutamine part in HTT interacts with various proteins implicated in epigenetic regulation of genes, suggesting that mutant HTT may disturb the integrity of the epigenetic system. Here, we used a PCRseq-based method to examine expression profile of 395 exonic segments from 260 "epi-driver" genes in splenic T lymphocytes from aged HD mice.

Alpha-Synuclein Suppresses Retinoic Acid-Induced Neuronal Differentiation by Targeting the Glycogen Synthase Kinase-3β/β-Catenin Signaling Pathway.

Alpha-synuclein (α-SYN) is expressed during neuronal development and is mainly involved in the modulation of synaptic transmission. Missense mutations and amplifications of this gene have been associated with the pathogenesis of Parkinson's disease. Here, we evaluate whether α-SYN plays a detrimental role in the phenotypic and morphological regulation of neurons.

Leucine-rich repeat kinase 2 exacerbates neuronal cytotoxicity through phosphorylation of histone deacetylase 3 and histone deacetylation.

Parkinson's disease (PD) is characterized by slow, progressive degeneration of dopaminergic neurons in the substantia nigra. The cause of neuronal death in PD is largely unknown, but several genetic loci, including leucine-rich repeat kinase 2 (LRRK2), have been identified. LRRK2 has guanosine triphosphatase (GTPase) and kinase activities, and mutations in LRRK2 are the major cause of autosomal-dominant familial PD.

G2385R and I2020T Mutations Increase LRRK2 GTPase Activity.

The LRRK2 mutation is a major causal mutation in familial Parkinson's disease. Although LRRK2 contains functional GTPase and kinase domains and their activities are altered by pathogenic mutations, most studies focused on LRRK2 kinase activity because the most prevalent mutant, G2019S, enhances kinase activity. However, the G2019S mutation is extremely rare in the Asian population.

β-Lapachone increases phase II antioxidant enzyme expression via NQO1-AMPK/PI3K-Nrf2/ARE signaling in rat primary astrocytes.

β-Lapachone (β-LAP) is a naturally occurring quinine that exerts a number of pharmacological actions including antibacterial, antifungal, antimalarial, and antitumor activities. In the present study, we investigated whether β-LAP has an antioxidant effect in rat primary astrocytes. β-LAP suppressed intracellular reactive oxygen species (ROS) production induced by hydrogen peroxide and inhibited astroglial cell death.

Leucine-Rich Repeat Kinase 2 (LRRK2) phosphorylates p53 and induces p21(WAF1/CIP1) expression.

Background: Leucine-rich repeat kinase 2 (LRRK2) is a gene in which a mutation causes Parkinson's disease (PD), and p53 is a prototype tumor suppressor. In addition, activation of p53 in patient with PD has been reported by several studies. Because phosphorylation of p53 is critical for regulating its activity and LRRK2 is a kinase, we tested whether p53 is phosphorylated by LRRK2.