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PubMed | National Defense Medical College, Teikyo Heisei University, Tokyo Metropolitan Institute of Medical Science, Institute of Neurological Disorders and Environmental Neuroscience Information Center
Type: Journal Article | Journal: International journal of environmental research and public health | Year: 2016

Neonicotinoids are considered safe because of their low affinities to mammalian nicotinic acetylcholine receptors (nAChRs) relative to insect nAChRs. However, because of importance of nAChRs in mammalian brain development, there remains a need to establish the safety of chronic neonicotinoid exposures with regards to childrens health. Here we examined the effects of longterm (14 days) and low dose (1 M) exposure of neuron-enriched cultures from neonatal rat cerebellum to nicotine and two neonicotinoids: acetamiprid and imidacloprid. Immunocytochemistry revealed no differences in the number or morphology of immature neurons or glial cells in any group versus untreated control cultures. However, a slight disturbance in Purkinje cell dendritic arborization was observed in the exposed cultures. Next we performed transcriptome analysis on total RNAs using microarrays, and identified significant differential expression (p < 0.05, q < 0.05, 1.5 fold) between control cultures versus nicotine-, acetamiprid-, or imidacloprid-exposed cultures in 34, 48, and 67 genes, respectively. Common to all exposed groups were nine genes essential for neurodevelopment, suggesting that chronic neonicotinoid exposure alters the transcriptome of the developing mammalian brain in a similar way to nicotine exposure. Our results highlight the need for further careful investigations into the effects of neonicotinoids in the developing mammalian brain.


News Article | December 1, 2016
Site: www.eurekalert.org

Charles Wilson, professor and Ewing Halsell Chair in Biology at The University of Texas at San Antonio (UTSA), has received an eight-year, grant from the U.S. Department of Health and Human Services expected to total $5,292,000. Wilson will receive the grant through the National Institutes of Health's (NIH) National Institute of Neurological Disorders and Stroke (NINDS), which aims to reduce the burden of neurological disease by supporting and conducting neuroscience research. Wilson's research focuses on the brain region involved in voluntary motor behavior, the basal ganglia. "This prestigious award from the U.S. Department of Health and Human Services is an immeasurable investment in brain health, which is a key research area not only for UTSA but also for the entire UT System. Dr. Wilson's research focus on the circuitry and function of neurons of the basal ganglia, which controls movement, will advance our understanding of degenerative disorders such Parkinson's disease. As a member of the UTSA Neurosciences Institute, Dr. Wilson is well deserving of this highly competitive NIH grant, and his top-tier research aligns with our Tier One goals," said Bernard Arulanandam, UTSA interim vice president for research. Wilson's research will examine local cell signaling in the basal ganglia to further develop a model of basal ganglia function. The goal of this modeling is to help improve current understanding of basal ganglia disorders and to assist in the development of potentially effective treatments. "With this substantial funding, UTSA will continue its leadership in brain health research and help the scientific community better understand, diagnose, treat and prevent neurological disorders like Parkinson's and Huntington's diseases. This work will help reduce folks' suffering and save lives," said U.S. Representative Joaquin Castro. "Thanks in large part to UTSA's impressive and expansive research programs, San Antonio is increasingly known as a city where science thrives. Our nation must never lose sight of the value of research, discovery, and knowledge. I'm proud that UTSA and the broader San Antonio community are leaders in learning, particularly in the field of brain health." The UTSA faculty includes 40 active researchers in brain health, an extensive initiative that includes research in neurodegenerative disease, traumatic brain injury, regenerative medicine, stem cell therapies, medicinal chemistry, neuroinflammation and drug design. This work is conducted across five top-tier research centers, including the UTSA Neurosciences Institute, the San Antonio Cellular Therapeutics Institute, the South Texas Center for Emerging Infectious Diseases, the Center for Innovative Drug Discovery and the Institute for Health Disparities Research. Leading the brain health revolution is one of UT System Chancellor William McRaven's "Quantum Leap" initiatives to provide the citizens of Texas the very best in higher education, research and health care. Chancellor McRaven has worked to make unprecedented investments in leveraging and connecting all the cutting edge science ongoing at UT institutions to drive collaboration and expand research efforts in brain health to meet a growing demand. The National Institute of Neurological Disorders and Stroke awarded the funding to UTSA through the Outstanding Investigator Award program. The program provides longer-term support to researchers whose records of achievement indicate their ability to make important contributions in the field of neuroscience. More stable grant funding gives recipients greater flexibility and freedom to conduct potentially groundbreaking research.


Katagiri S.,Jikei University School of Medicine | Gekka T.,Jikei University School of Medicine | Hayashi T.,Jikei University School of Medicine | Ida H.,Jikei University School of Medicine | And 3 more authors.
Documenta Ophthalmologica | Year: 2014

Background: Gyrate atrophy (GA) of the choroid and retina is an extremely rare inherited chorioretinal dystrophy. Ornithine aminotransferase (OAT) gene mutations are identified in patients with GA. The purpose of this study was to report a novel deletion mutation of the OAT gene and describe clinical features of two brothers with GA in a Japanese family. Methods: We performed ophthalmic examinations, including best-corrected visual acuity, slit-lamp biomicroscopy, dilated funduscopy, fundus autofluorescence imaging, optical coherence tomography, visual field testing, and full-field electroretinography (ERG). Serum ornithine concentrations and OAT activities were analyzed. Mutation screening of the OAT gene was performed using Sanger sequencing. Results: Both brothers had compound heterozygous mutations (p.K169DfsX10 and p.R426X), one of which was novel. Their unaffected parents carried one of the mutations heterozygously. An arginine-restricted diet was started in the younger brother at the age of 2 years, while the diet was not initiated in the older brother until the age of 6 years. After more than 15 years of follow-up, the dietary treatment seemed to slow the progression of the chorioretinal lesions in the younger brother. However, when compared at the same age, the younger brother had more reduced ERG amplitudes and constricted visual fields than his older brother. Conclusions: We identified a novel frameshift mutation (p.K169DfsX10) in the OAT gene. While an early arginine-restricted dietary treatment suppressed the fundus changes of GA to some degree in the younger brother, the efficacy of suppressing the progression of visual function loss could not be clearly determined. © 2014 Springer-Verlag.


Wakabayashi T.,Jikei University School of Medicine | Shimada Y.,Jikei University School of Medicine | Akiyama K.,Kitasato University | Higuchi T.,Jikei University School of Medicine | And 5 more authors.
Human Gene Therapy | Year: 2015

Mucopolysaccharidosis type II (MPS II) is a neuropathic lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS), which leads to the accumulation of glycosaminoglycans (GAGs). We demonstrated that biochemical alterations in the brains of MPS II mice are not corrected by bone marrow transplantation (BMT) or enzyme replacement therapy, although BMT has been shown to be effective for other neurodegenerative MPSs, such as Hurler syndrome. In this study, we demonstrated that lentiviral isogeneic hematopoietic stem cell (HSC) gene therapy corrected neuronal manifestations by ameliorating lysosomal storage and autophagic dysfunction in the brains of MPS II mice. IDS-transduced HSCs increased enzyme activity both in various visceral organs and the CNS. Decreased levels of GAGs were observed in many organs, including cerebra, after transplantation of IDS-transduced HSCs. In addition, lentiviral HSC gene therapy normalized the secondary accumulation of autophagic substrates, such as p62 and ubiquitin-protein conjugates, in cerebra. Furthermore, in contrast to naive MPS II mice, there was no deterioration of neuronal function observed in transplant recipients. These results indicated that lentiviral HSC gene therapy is a promising approach for the treatment of CNS lesions in MPS II. Copyright 2015, Mary Ann Liebert, Inc.


Kawagoe S.,Jikei University School of Medicine | Higuchi T.,Jikei University School of Medicine | Otaka M.,Japan National Institute of Advanced Industrial Science and Technology | Shimada Y.,Jikei University School of Medicine | And 7 more authors.
Molecular Genetics and Metabolism | Year: 2013

We generated iPS cells from human dermal fibroblasts (HDFs) of Fabry disease using a Sendai virus (SeVdp) vector; this method has been established by Nakanishi et al. for pathogenic evaluation. We received SeVdp vector from Nakanishi and loaded it simultaneously with four reprogramming factors (Klf4, Oct4, Sox2, and c-Myc) to HDFs of Fabry disease; subsequently, we observed the presence of human iPS-like cells. The Sendai virus nucleocapsid protein was not detected in the fibroblasts by RT-PCR analysis. Additionally, we confirmed an undifferentiated state, alkaline phosphatase staining, and the presence of SSEA-4, TRA-1-60, and TRA-1-81. Moreover, ultrastructural features of these iPS cells included massive membranous cytoplasmic bodies typical of HDFs of Fabry disease. Thus, we successfully generated human iPS cells from HDFs of Fabry disease that retained the genetic conditions of Fabry disease; also, these abnormal iPS cells could not be easily differentiated into mature cell types such as neuronal cells, cardiomyocytes, etc. because of a massive accumulation of membranous cytoplasmic bodies in lysosomes, possibly the persistent damages of intracellular architecture. © 2013 Elsevier Inc.


PubMed | Jikei University School of Medicine and Institute of Neurological Disorders
Type: Journal Article | Journal: Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association | Year: 2016

Fabry disease (FD) is an X-linked lysosomal storage disorder frequently associated with the central nervous system manifestations. Although white matter hyperintensity (WMH) on MRI has been previously reported, little is known about cerebral microbleeds (CMBs) in patients with FD. Our aim is to investigate the clinical characteristics of CMBs in patients with FD.All patients with FD were diagnosed by enzyme activity and/or gene analysis at Jikei University Hospital. We retrospectively enrolled consecutive patients with FD who underwent MRI study, including fluid-attenuated inversion recovery and susceptibility-weighted imaging, between July 2008 and September 2013. After categorizing the patients into CMB-positive and CMB-negative groups, we compared the clinical characteristics between the 2 groups.We enrolled 54 patients (males, 24; median age 39 years, interquartile range; 29-50 years). The CMB-positive group included 16 (30%) patients. The number of males was significantly higher in the CMB-positive group than in the CMB-negative group (75% versus 32%, P=.003). The prevalence rates of chronic kidney disease (CKD) (estimated glomerular filtration rate<60mL/min/1.73m(2)) and WMH were higher in the CMB-positive group than in the CMB-negative group (CKD: 44% versus 13%, P=.013; WMH: 88% versus 58%, P=.035). No significant differences in the number of vascular risk factors were observed between the 2 groups.The distinct characteristics of FD patients with CMBs were male sex, presence of CKD, and WMH. These factors may play an important role in the mechanism of hemorrhagic stroke in FD.


PubMed | Jikei University School of Medicine and Institute of Neurological Disorders
Type: Journal Article | Journal: Molecular genetics and metabolism | Year: 2016

Mucopolysaccharidosis type II (MPS II) is an X-linked lysosomal storage disorder arising from deficiency of iduronate-2-sulfatase (IDS), which results in progressive accumulation of glycosaminoglycans (GAGs) in multiple tissues. Accumulated GAGs are generally measured as the amount of total GAGs. However, we recently demonstrated that GAG accumulation in the brain of MPS II model mice cannot be reliably detected by conventional dye-binding assay measuring total GAGs. Here we developed a novel quantitative method for measurement of disease-specific GAGs based on the analysis of 2-sulfoiduronic acid levels derived from the non-reducing terminal end of the polysaccharides by using recombinant human IDS (rhIDS) and recombinant human iduronidase (rhIDUA). This method was evaluated on GAGs obtained from the liver and brain of MPS II mice. The GAGs were purified from tissue homogenates and then digested with rhIDS and rhIDUA to generate a desulfated iduronic acid from their non-reducing terminal end. HPLC analysis revealed that the generated iduronic acid levels were markedly increased in the liver and cerebrum of the MPS II mice, whereas the uronic acid was not detected in wild-type mice. These results indicate that this assay clearly detects the disease-specific GAGs in tissues from MPS II mice.


PubMed | Kitasato University, Jikei University School of Medicine and Institute of Neurological Disorders
Type: Journal Article | Journal: Human gene therapy | Year: 2015

Mucopolysaccharidosis type II (MPS II) is a neuropathic lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS), which leads to the accumulation of glycosaminoglycans (GAGs). We demonstrated that biochemical alterations in the brains of MPS II mice are not corrected by bone marrow transplantation (BMT) or enzyme replacement therapy, although BMT has been shown to be effective for other neurodegenerative MPSs, such as Hurler syndrome. In this study, we demonstrated that lentiviral isogeneic hematopoietic stem cell (HSC) gene therapy corrected neuronal manifestations by ameliorating lysosomal storage and autophagic dysfunction in the brains of MPS II mice. IDS-transduced HSCs increased enzyme activity both in various visceral organs and the CNS. Decreased levels of GAGs were observed in many organs, including cerebra, after transplantation of IDS-transduced HSCs. In addition, lentiviral HSC gene therapy normalized the secondary accumulation of autophagic substrates, such as p62 and ubiquitin-protein conjugates, in cerebra. Furthermore, in contrast to naive MPS II mice, there was no deterioration of neuronal function observed in transplant recipients. These results indicated that lentiviral HSC gene therapy is a promising approach for the treatment of CNS lesions in MPS II.


PubMed | Jikei University School of Medicine and Institute of Neurological Disorders
Type: | Journal: Molecular genetics and metabolism reports | Year: 2016

We examined alpha-galactosidase A (GLA) gene mutations in 74 Japanese families with Fabry disease (FD) to determine the frequency of


PubMed | Jikei University School of Medicine, Tokyo Medical University, Institute of Neurological Disorders and BioMarin Pharmaceutical
Type: Journal Article | Journal: Molecular genetics and metabolism | Year: 2014

Before the availability of an enzyme replacement therapy (ERT) for mucopolysaccharidosis type II (MPS II), patients were treated by bone marrow transplantation (BMT). However, the effectiveness of BMT for MPS II was equivocal, particularly at addressing the CNS manifestations. To study this further, we subjected a murine model of MPS II to BMT and evaluated the effect at correcting the biochemical and pathological aberrations in the viscera and CNS. Our results indicated that BMT reduced the accumulation of glycosaminoglycans (GAGs) in a variety of visceral organs, but not in the CNS. With the availability of an approved ERT for MPS II, we investigated and compared the relative merits of the two strategies either as a mono or combination therapy. We showed that the combination of BMT and ERT was additive at reducing tissue levels of GAGs in the heart, kidney and lung. Moreover, ERT conferred greater efficacy if the immunological response against the infused recombinant enzyme was low. Finally, we showed that pathologic GAGs might potentially represent a sensitive biomarker to monitor the therapeutic efficacy of therapies for MPS II.

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