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Dive into the research topics where Christine Iwahashi is active.

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Featured researches published by Christine Iwahashi.


RNA Biology | 2004

FMR1 RNA within the intranuclear inclusions of fragile X-associated tremor/ataxia syndrome (FXTAS).

Flora Tassone; Christine Iwahashi; Paul J. Hagerman

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently identified neurodegenerative disorder affecting older adult males with premutation alleles of the fragile X mental retardation 1 (FMR1) gene. The principal clinical features of FXTAS include progressive intention tremor, gait ataxia, parkinsonism, and autonomic dysfunction. The disorder affects at least one-third of carrier males over 50 years of age and, with an estimated carrier frequency of ~1/800 males, is likely to be one of the most common heritable forms of tremor and ataxia among older adult males in the general population. Brains from all FXTAS cases examined to date (10/10) possess numerous ubiquitin-positive intranuclear inclusions in broad distribution throughout the cerebrum and brainstem. The absence of either the neurodegenerative disorder or inclusions among adults with fragile X syndrome (who lack the FMR1 protein), coupled with elevated FMR1 mRNA with expanded CGG repeats in premutation carriers, has led us to propose an RNA toxic gain-of-function model for FXTAS. Consistent with this model, we have now identified FMR1 mRNA within the intranuclear inclusions isolated from post-mortem (FXTAS) brain tissue.


Biological Psychiatry | 2011

Decreased fragile x mental retardation protein expression underlies amygdala dysfunction in carriers of the fragile x premutation

David Hessl; John M. Wang; Andrea Schneider; Kami Koldewyn; Lien Le; Christine Iwahashi; Katherine Cheung; Flora Tassone; Paul J. Hagerman; Susan M. Rivera

BACKGROUND The fragile X premutation provides a unique opportunity for the study of genetic and brain mechanisms of behavior and cognition in the context of neurodevelopment and neurodegeneration. Although the neurodegenerative phenotype, fragile X-associated tremor/ataxia syndrome, is well described, evidence of a causal link between the premutation and psychiatric disorder earlier in life, clear delineation of a behavioral/cognitive phenotype, and characterization of the physiological basis of observed symptoms have been elusive. METHODS We completed functional magnetic resonance imaging targeting the amygdala with an emotion-matching task and concurrent infrared eye tracking, FMR1 molecular genetic testing, and neuropsychological assessment in 23 men with the premutation (mean age = 32.9 years) and 25 male control subjects (mean age = 30.1 years). RESULTS Premutation carriers had significantly smaller left and right amygdala volume and reduced right amygdala activation during the task relative to control subjects. Although both elevated FMR1 messenger RNA and reduced fragile X mental retardation protein (FMRP) were associated with the reduced activation, multiple regression analysis suggested that reduced FMRP is the primary factor. Premutation carriers also had higher ratings of autism spectrum symptoms than control subjects, which were associated with the reduced amygdala response. CONCLUSIONS Although prior studies have emphasized a toxic gain-of-function effect of elevated messenger RNA associated with the premutation, the current results point to the role of reduced FMRP in alterations of brain activity and behavior.


Cancer Letters | 2001

Whole almonds and almond fractions reduce aberrant crypt foci in a rat model of colon carcinogenesis

Paul A. Davis; Christine Iwahashi

Almonds and other nuts appear to confer health benefits despite their high fat content. To assess the effect of almonds on colon cancer, whole almond-, almond meal- or almond oil-containing diet effects on aberrant crypt foci (ACF) in azoxymethane-treated F344 male rats were investigated. Six-week-old male F344 rats were fed the various almond and control diets and given subcutaneous injections of azoxymethane (15 mg/kg body weight) twice 1 week apart. After 26 weeks animals were injected with bromodeoxyuridine 1 h prior to sacrifice, after which colons were evaluated for ACF and cell turnover (labeling index, LI). Whole almond ACF and LI were both significantly lower than wheat bran and cellulose diet groups (-30 and -40%, respectively), while almond meal and almond oil ACF and almond meal LI declines were only significant vs. cellulose (P<0.05). These results suggest that almond consumption may reduce colon cancer risk and does so via at least one almond lipid-associated component.


Human Molecular Genetics | 2011

ALTERED ZINC TRANSPORT DISRUPTS MITOCHONDRIAL PROTEIN PROCESSING/IMPORT IN FRAGILE X-ASSOCIATED TREMOR/ATAXIA SYNDROME

Eleonora Napoli; Catherine Ross-Inta; Sarah Wong; Alicja Omanska-Klusek; Cedrick Barrow; Christine Iwahashi; Danielle Sakaguchi; Elizabeth Berry-Kravis; Randi J. Hagerman; Paul J. Hagerman; Cecilia Giulivi

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects individuals who are carriers of small CGG premutation expansions in the fragile X mental retardation 1 (FMR1) gene. Mitochondrial dysfunction was observed as an incipient pathological process occurring in individuals who do not display overt features of FXTAS (1). Fibroblasts from premutation carriers had lower oxidative phosphorylation capacity (35% of controls) and Complex IV activity (45%), and higher precursor-to-mature ratios (P:M) of nDNA-encoded mitochondrial proteins (3.1-fold). However, fibroblasts from carriers with FXTAS symptoms presented higher FMR1 mRNA expression (3-fold) and lower Complex V (38%) and aconitase activities (43%). Higher P:M of ATPase β-subunit (ATPB) and frataxin were also observed in cortex from patients that died with FXTAS symptoms. Biochemical findings observed in FXTAS cells (lower mature frataxin, lower Complex IV and aconitase activities) along with common phenotypic traits shared by Friedreichs ataxia and FXTAS carriers (e.g. gait ataxia, loss of coordination) are consistent with a defective iron homeostasis in both diseases. Higher P:M, and lower ZnT6 and mature frataxin protein expression suggested defective zinc and iron metabolism arising from altered ZnT protein expression, which in turn impairs the activity of mitochondrial Zn-dependent proteases, critical for the import and processing of cytosolic precursors, such as frataxin. In support of this hypothesis, Zn-treated fibroblasts showed a significant recovery of ATPB P:M, ATPase activity and doubling time, whereas Zn and desferrioxamine extended these recoveries and rescued Complex IV activity.


Human Molecular Genetics | 2010

Fibroblast phenotype in male carriers of FMR1 premutation alleles

Jane E. Yang; Judith R. Brouwer; Flora Tassone; Christine Iwahashi; Elizabeth Berry-Kravis; Christopher G. Goetz; Allison Sumis; Lili Zhou; Danh V. Nguyen; Luis Campos; Erin Howell; Anna L. Ludwig; Claudia M. Greco; Rob Willemsen; Randi J. Hagerman; Paul J. Hagerman

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder among carriers of premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. The clinical features of FXTAS, as well as various forms of clinical involvement in carriers without FXTAS, are thought to arise through a direct toxic gain of function of high levels of FMR1 mRNA containing the expanded CGG repeat. Here we report a cellular endophenotype involving increased stress response (HSP27, HSP70 and CRYAB) and altered lamin A/C expression/organization in cultured skin fibroblasts from 11 male carriers of premutation alleles of the FMR1 gene, including six patients with FXTAS and five premutation carriers with no clinical evidence of FXTAS, compared with six controls. A similar abnormal cellular phenotype was found in CNS tissue from 10 patients with FXTAS. Finally, there is an analogous abnormal cellular distribution of lamin A/C isoforms in knock-in mice bearing the expanded CGG repeat in the murine Fmr1 gene. These alterations are evident even in mouse embryonic fibroblasts, raising the possibility that, in humans, the expanded-repeat mRNA triggers pathogenic mechanisms early in development, thus providing a molecular basis for the neurodevelopmental abnormalities observed in some children and clinical symptoms in some adults who are carriers of premutation FMR1 alleles. Cellular dysregulation in fibroblasts represents a novel and highly advantageous model for investigating disease pathogenesis in premutation carriers and for quantifying and monitoring disease progression. Fibroblast studies may also prove useful in screening and testing the efficacy of therapeutic interventions.


The Journal of Molecular Diagnostics | 2009

A Quantitative ELISA Assay for the Fragile X Mental Retardation 1 Protein

Christine Iwahashi; Flora Tassone; Randi J. Hagerman; Dag H. Yasui; George Parrott; Danh V. Nguyen; Greg L. Mayeur; Paul J. Hagerman

Non-coding (CGG-repeat) expansions in the fragile X mental retardation 1 (FMR1) gene result in a spectrum of disorders involving altered neurodevelopment (fragile X syndrome), neurodegeneration (late-onset fragile X-associated tremor/ataxia syndrome), or primary ovarian insufficiency. While reliable and quantitative assays for the number of CGG repeats and FMR1 mRNA levels are now available, there has been no scalable, quantitative assay for the FMR1 protein (FMRP) in non-transformed cells. Using a combination of avian and murine antibodies to FMRP, we developed a sensitive and highly specific sandwich enzyme-linked immunosorbent assay (ELISA) for FMRP in peripheral blood lymphocytes. This ELISA method is capable of quantifying FMRP levels throughout the biologically relevant range of protein concentrations and is specific for the intact FMRP protein. Moreover, the ELISA is well-suited for replicate protein determinations across serial dilutions in non-transformed cells and is readily scalable for large sample numbers. The FMRP ELISA is potentially a powerful tool in expanding our understanding of the relationship between FMRP levels and the various FMR1-associated clinical phenotypes.


Human Molecular Genetics | 2011

CGG-repeat length threshold for FMR1 RNA pathogenesis in a cellular model for FXTAS

Gry Hoem; Christopher Raske; Flora Tassone; Eleonora Sanchez; Anna L. Ludwig; Christine Iwahashi; Madhur Kumar; Jane E. Yang; Paul J. Hagerman

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that affects carriers of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. The presence of elevated levels of expanded mRNA found in premutation carriers is believed to be the basis for the pathogenesis in FXTAS, but the exact mechanisms by which the mRNA causes toxicity are not known. In particular, it is not clear whether there is a threshold for a CGG-repeat number below which no cellular dysregulation occurs, or whether toxicity depends on mRNA concentration. We have developed a doxycycline-inducible episomal system that allows us to study separately the effects of CGG-repeat number and mRNA concentration (at fixed CGG-repeat length) in neuroblastoma-derived SK cells. Our findings show that there is a CGG-repeat size threshold for toxicity that lies between 62 and 95 CGG repeats. Interestingly, for repeat sizes of 95 CGG and above, there is a clear negative correlation between mRNA concentration and cell viability. Taken together, our results provide evidence for an RNA-toxicity model with primary dependence on CGG-repeat size and secondary dependence on mRNA concentration, thus formally ruling out any simple titration model that operates in the absence of either protein-binding cooperativity or some form of length-dependent RNA structural transition.


Free Radical Biology and Medicine | 1998

Redox regulation of wound healing? NF-κB activation in cultured human keratinocytes upon wounding and the effect of low energy HeNe irradiation

Ann F. Haas; Jon W. Wong; Christine Iwahashi; Barry Halliwell; Carroll E. Cross; Paul A. Davis

The complex process of wound healing as well as the signaling systems orchestrating this intricate process remain incompletely defined. Using human keratinocytes in primary culture, we sought to characterize their NF-kappaB responses to wounding alone or in combination with other treatments. We initially characterized these cultured human keratinocytes responses to known NF-kappaB activators (PMA, TNF-alpha and IL-1) using two different assays, immunohistochemistry and electrophoretic mobility shift (EMSA). After eliciting the expected NF-kappaB responses, we applied these same assays to assess responses to either wounding or HeNe irradiation alone. The results obtained indicated that only a modest/sporadic activation of NF-kappaB was elicited by these which was only detectable using immunohistochemistry. When the combination of wounding and HeNe irradiation on NF-kappaB status was assessed, a marked, localized activation of NF-kappaB in keratinocytes along the wound edge was found. Treatment induced NF-kappaB activation (e.g., wounding, HeNe irradiation and combined wounding and HeNe irradiation) was abrogated by pyrrolidine dithiocarbamate (PDTC) which inhibits NF-kappaB activation through an as yet incompletely understood (antioxidant?) mechanism. These data therefore suggest that NF-kappaB and oxidation mediated changes in its activation state likely play important roles in normal cutaneous wound healing.


NeuroImage | 2013

Influence of the fragile X mental retardation (FMR1) gene on the brain and working memory in men with normal FMR1 alleles

Jun Yi Wang; David Hessl; Christine Iwahashi; Katherine Cheung; Andrea Schneider; Randi J. Hagerman; Paul J. Hagerman; Susan M. Rivera

The fragile X mental retardation 1 (FMR1) gene plays an important role in the development and maintenance of neuronal circuits that are essential for cognitive functioning. We explored the functional linkage(s) among lymphocytic FMR1 gene expression, brain structure, and working memory in healthy adult males. We acquired T1-weighted and diffusion tensor imaging from 37 males (18-80 years, mean ± SD= 40.7 ± 17.3 years) with normal FMR1 alleles and performed genetic and working memory assessments. Brain measurements were obtained from fiber tracts important for working memory (i.e. the arcuate fasciculus, anterior cingulum bundle, inferior longitudinal fasciculus, and the genu and anterior body of the corpus callosum), individual voxels, and whole brain. Both FMR1 mRNA and protein (FMRP) levels exhibited significant associations with brain measurements, with FMRP correlating positively with gray matter volume and white matter structural organization, and FMR1 mRNA negatively with white matter structural organization. The correlation was widespread, impacting rostral white matter and 2 working-memory fiber tracts for FMRP, and all cerebral white matter areas except the fornix and cerebellar peduncles and all 4 fiber tracts for FMR1 mRNA. In addition, the levels of FMR1 mRNA as well as the fiber tracts demonstrated a significant correlation with working memory performance. While FMR1 mRNA exhibited a negative correlation with working memory, fiber tract structural organization showed a positive correlation. These findings suggest that the FMR1 gene is a genetic factor common for both working memory and brain structure, and has implications for our understanding of the transmission of intelligence and brain structure.


Retina-the Journal of Retinal and Vitreous Diseases | 1997

Apolipoprotein E in the subretinal fluid of rhegmatogenous and exudative retinal detachments.

Simon A. Schneeberger; Christine Iwahashi; Leonard M. Hjelmeland; Paul A. Davis; Lawrence S. Morse

BACKGROUND Apolipoprotein E plays a key role in lipoprotein metabolism and is believed to be an important protein in other biologic functions such as wound healing processes of nerve tissue. Because the neurosensory retina is rich in lipids, we analyzed the subretinal fluid from patients with acute and chronic retinal detachments to determine whether apolipoprotein was present and whether it was involved in lipid metabolism during wound repair of the detached retina. METHODS The subretinal fluid collected from eyes with rhegmatogenous and exudative retinal detachments first was analyzed by agarose and sodium dodecyl sulfate gel electrophoresis to identify the lipoprotein profiles. Western blot analysis confirmed the presence of apolipoprotein E, and semiquantitation was performed by densitometry of the corresponding immunodot-blot. RESULTS Apolipoprotein E was present in the subretinal fluid of eyes with rhegmatogenous and exudative retinal detachments. Its concentration increased in eyes with chronic retinal detachments. CONCLUSIONS We implicate apolipoprotein E found in the subretinal fluid in the wound-healing process of the detached retina.

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Paul J. Hagerman

Boston Children's Hospital

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Randi J. Hagerman

California State University

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Flora Tassone

Boston Children's Hospital

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Danh V. Nguyen

University of California

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Anna L. Ludwig

University of California

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Dag H. Yasui

University of California

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Elizabeth Berry-Kravis

Rush University Medical Center

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Paul A. Davis

University of California

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