Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features.

Abstract:

:The 'neurodegeneration with brain iron accumulation' (NBIA) disease family entails movement or cognitive impairment, often with psychiatric features. To understand how iron loading affects the brain, we studied mice with disruption of two iron regulatory genes, hemochromatosis (Hfe) and transferrin receptor 2 (Tfr2). Inductively coupled plasma atomic emission spectroscopy demonstrated increased iron in the Hfe-/- × Tfr2mut brain (P=0.002, n ≥5/group), primarily localized by Perls' staining to myelinated structures. Western immunoblotting showed increases of the iron storage protein ferritin light polypeptide and microarray and real-time reverse transcription-PCR revealed decreased transcript levels (P<0.04, n ≥5/group) for five other NBIA genes, phospholipase A2 group VI, fatty acid 2-hydroxylase, ceruloplasmin, chromosome 19 open reading frame 12 and ATPase type 13A2. Apart from the ferroxidase ceruloplasmin, all are involved in myelin homeostasis; 16 other myelin-related genes also showed reduced expression (P<0.05), although gross myelin structure and integrity appear unaffected (P>0.05). Overlap (P<0.0001) of differentially expressed genes in Hfe-/- × Tfr2mut brain with human gene co-expression networks suggests iron loading influences expression of NBIA-related and myelin-related genes co-expressed in normal human basal ganglia. There was overlap (P<0.0001) of genes differentially expressed in Hfe-/- × Tfr2mut brain and post-mortem NBIA basal ganglia. Hfe-/- × Tfr2mut mice were hyperactive (P<0.0112) without apparent cognitive impairment by IntelliCage testing (P>0.05). These results implicate myelin-related systems involved in NBIA neuropathogenesis in early responses to iron loading. This may contribute to behavioral symptoms in NBIA and hemochromatosis and is relevant to patients with abnormal iron status and psychiatric disorders involving myelin abnormalities or resistant to conventional treatments.

journal_name

Mol Psychiatry

journal_title

Molecular psychiatry

authors

Heidari M,Johnstone DM,Bassett B,Graham RM,Chua AC,House MJ,Collingwood JF,Bettencourt C,Houlden H,Ryten M,Olynyk JK,Trinder D,Milward EA

doi

10.1038/mp.2015.192

subject

Has Abstract

pub_date

2016-11-01 00:00:00

pages

1599-1607

issue

11

eissn

1359-4184

issn

1476-5578

pii

mp2015192

journal_volume

21

pub_type

杂志文章
  • Dietary triglycerides act on mesolimbic structures to regulate the rewarding and motivational aspects of feeding.

    abstract::Circulating triglycerides (TGs) normally increase after a meal but are altered in pathophysiological conditions, such as obesity. Although TG metabolism in the brain remains poorly understood, several brain structures express enzymes that process TG-enriched particles, including mesolimbic structures. For this reason,...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2014.31

    authors: Cansell C,Castel J,Denis RG,Rouch C,Delbes AS,Martinez S,Mestivier D,Finan B,Maldonado-Aviles JG,Rijnsburger M,Tschöp MH,DiLeone RJ,Eckel RH,la Fleur SE,Magnan C,Hnasko TS,Luquet S

    更新日期:2014-10-01 00:00:00

  • Identification of a polymorphism in the promoter region of DRD4 associated with the human novelty seeking personality trait.

    abstract::Polymorphism in the human dopamine D4 receptor gene (DRD4) exon III has been associated in some but not all studies of the human personality trait of Novelty Seeking. We searched for polymorphisms in the 5' region of DRD4 and identified six polymorphisms as follows: -1217G Ins/Del, -809G/A, -616C/G, -603T Ins/Del, -60...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/sj.mp.4000563

    authors: Okuyama Y,Ishiguro H,Nankai M,Shibuya H,Watanabe A,Arinami T

    更新日期:2000-01-01 00:00:00

  • Active vaccination with ankyrin G reduces β-amyloid pathology in APP transgenic mice.

    abstract::Serum antibodies against amyloid-β peptide (Aβ) in humans with or without diagnosis of Alzheimer's disease (AD) indicate the possibility of immune responses against brain antigens. In an unbiased screening for antibodies directed against brain proteins, we found in AD patients high serum levels of antibodies against t...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2012.70

    authors: Santuccione AC,Merlini M,Shetty A,Tackenberg C,Bali J,Ferretti MT,McAfoose J,Kulic L,Bernreuther C,Welt T,Grimm J,Glatzel M,Rajendran L,Hock C,Nitsch RM

    更新日期:2013-03-01 00:00:00

  • Sex, trauma, stress hormones and depression.

    abstract::Although few studies dispute that there are gender differences in depression, the etiology is still unknown. In this review, we cover a number of proposed factors and the evidences for and against these factors that may account for gender differences in depression. These include the possible role of estrogens at puber...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章,评审

    doi:10.1038/mp.2009.94

    authors: Young E,Korszun A

    更新日期:2010-01-01 00:00:00

  • Dopamine D4 receptor, but not the ADHD-associated D4.7 variant, forms functional heteromers with the dopamine D2S receptor in the brain.

    abstract::Polymorphic variants of the dopamine D(4) receptor have been consistently associated with attention-deficit hyperactivity disorder (ADHD). However, the functional significance of the risk polymorphism (variable number of tandem repeats in exon 3) is still unclear. Here, we show that whereas the most frequent 4-repeat ...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2011.93

    authors: González S,Rangel-Barajas C,Peper M,Lorenzo R,Moreno E,Ciruela F,Borycz J,Ortiz J,Lluís C,Franco R,McCormick PJ,Volkow ND,Rubinstein M,Floran B,Ferré S

    更新日期:2012-06-01 00:00:00

  • FKBP51 inhibits GSK3β and augments the effects of distinct psychotropic medications.

    abstract::Psychotropic medications target glycogen synthase kinase 3β (GSK3β), but the functional integration with other factors relevant for drug efficacy is poorly understood. We discovered that the suggested psychiatric risk factor FK506 binding protein 51 (FKBP51) increases phosphorylation of GSK3β at serine 9 (pGSK3β(S9))....

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2015.38

    authors: Gassen NC,Hartmann J,Zannas AS,Kretzschmar A,Zschocke J,Maccarrone G,Hafner K,Zellner A,Kollmannsberger LK,Wagner KV,Mehta D,Kloiber S,Turck CW,Lucae S,Chrousos GP,Holsboer F,Binder EB,Ising M,Schmidt MV,Rein T

    更新日期:2016-02-01 00:00:00

  • The birth, death and resurrection of avoidance: a reconceptualization of a troubled paradigm.

    abstract::Research on avoidance conditioning began in the late 1930s as a way to use laboratory experiments to better understand uncontrollable fear and anxiety. Avoidance was initially conceived of as a two-factor learning process in which fear is first acquired through Pavlovian aversive conditioning (so-called fear condition...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章,评审

    doi:10.1038/mp.2016.166

    authors: LeDoux JE,Moscarello J,Sears R,Campese V

    更新日期:2017-01-01 00:00:00

  • Vulnerability genes or plasticity genes?

    abstract::The classic diathesis-stress framework, which views some individuals as particularly vulnerable to adversity, informs virtually all psychiatric research on behavior-gene-environment (G x E) interaction. An alternative framework of 'differential susceptibility' is proposed, one which regards those most susceptible to a...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章,评审

    doi:10.1038/mp.2009.44

    authors: Belsky J,Jonassaint C,Pluess M,Stanton M,Brummett B,Williams R

    更新日期:2009-08-01 00:00:00

  • Nuclear receptor corepressors in intellectual disability and autism.

    abstract::Autism spectrum disorder (ASD) is characterized by neurocognitive dysfunctions, such as impaired social interaction and language learning. Gene-environment interactions have a pivotal role in ASD pathogenesis. Nuclear receptor corepressors (NCORs) are transcription co-regulators physically associated with histone deac...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章,评审

    doi:10.1038/s41380-020-0667-y

    authors: Kong Y,Zhou W,Sun Z

    更新日期:2020-10-01 00:00:00

  • Altered temporal, but intact spatial, features of transient network dynamics in psychosis.

    abstract::Contemporary models of psychosis suggest that a continuum of severity of psychotic symptoms exists, with subthreshold psychotic experiences (PEs) potentially reflecting some genetic and environmental risk factors shared with clinical psychosis. Thus, identifying abnormalities in brain activity that manifest across thi...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/s41380-020-00983-1

    authors: Wang D,Peng X,Pelletier-Baldelli A,Orlov N,Farabaugh A,Nasr S,Eryilmaz H,Fava M,Holmes AJ,Roffman JL,Liu H,Holt DJ

    更新日期:2021-01-18 00:00:00

  • Transcranial direct current stimulation: a roadmap for research, from mechanism of action to clinical implementation.

    abstract::Transcranial direct current stimulation (tDCS) is a promising method for altering the function of neural systems, cognition, and behavior. Evidence is emerging that it can also influence psychiatric symptomatology, including major depression and schizophrenia. However, there are many open questions regarding how the m...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章,评审

    doi:10.1038/s41380-019-0499-9

    authors: Chase HW,Boudewyn MA,Carter CS,Phillips ML

    更新日期:2020-02-01 00:00:00

  • A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight.

    abstract::Schizophrenia is a chronic, severe and highly complex mental illness. Current treatments manage the positive symptoms, yet have minimal effects on the negative and cognitive symptoms, two prominent features of the disease with critical impact on the long-term morbidity. In addition, antipsychotic treatments trigger se...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2012.57

    authors: Revel FG,Moreau JL,Pouzet B,Mory R,Bradaia A,Buchy D,Metzler V,Chaboz S,Groebke Zbinden K,Galley G,Norcross RD,Tuerck D,Bruns A,Morairty SR,Kilduff TS,Wallace TL,Risterucci C,Wettstein JG,Hoener MC

    更新日期:2013-05-01 00:00:00

  • Positive psychotic symptoms are associated with divergent developmental trajectories of hippocampal volume during late adolescence in patients with 22q11DS.

    abstract::Low hippocampal volume is a consistent finding in schizophrenia and across the psychosis spectrum. However, there is a lack of studies investigating longitudinal hippocampal development and its relationship with psychotic symptoms. The 22q11.2 deletion syndrome (22q11DS) has proven to be a remarkable model for the pro...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/s41380-019-0443-z

    authors: Mancini V,Sandini C,Padula MC,Zöller D,Schneider M,Schaer M,Eliez S

    更新日期:2020-11-01 00:00:00

  • The bacterial peptidoglycan-sensing molecule Pglyrp2 modulates brain development and behavior.

    abstract::Recent studies have revealed that the gut microbiota modulates brain development and behavior, but the underlying mechanisms are still poorly understood. Here, we show that bacterial peptidoglycan (PGN) derived from the commensal gut microbiota can be translocated into the brain and sensed by specific pattern-recognit...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2016.182

    authors: Arentsen T,Qian Y,Gkotzis S,Femenia T,Wang T,Udekwu K,Forssberg H,Diaz Heijtz R

    更新日期:2017-02-01 00:00:00

  • HPA axis in major depression: cortisol, clinical symptomatology and genetic variation predict cognition.

    abstract::The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of a variety of mood and cognitive disorders. Neuroendocrine studies have demonstrated HPA axis overactivity in major depression, a relationship of HPA axis activity to cognitive performance and a potential role of HPA axis geneti...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2016.120

    authors: Keller J,Gomez R,Williams G,Lembke A,Lazzeroni L,Murphy GM Jr,Schatzberg AF

    更新日期:2017-04-01 00:00:00

  • Treatment response prediction and individualized identification of first-episode drug-naïve schizophrenia using brain functional connectivity.

    abstract::Identifying biomarkers in schizophrenia during the first episode without the confounding effects of treatment has been challenging. Leveraging these biomarkers to establish diagnosis and make individualized predictions of future treatment responses to antipsychotics would be of great value, but there has been limited ...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/s41380-018-0106-5

    authors: Cao B,Cho RY,Chen D,Xiu M,Wang L,Soares JC,Zhang XY

    更新日期:2020-04-01 00:00:00

  • Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.

    abstract::DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/s41380-019-0605-z

    authors: Jia T,Chu C,Liu Y,van Dongen J,Papastergios E,Armstrong NJ,Bastin ME,Carrillo-Roa T,den Braber A,Harris M,Jansen R,Liu J,Luciano M,Ori APS,Roiz Santiañez R,Ruggeri B,Sarkisyan D,Shin J,Sungeun K,Tordesillas Gutiérre

    更新日期:2019-12-06 00:00:00

  • Altered connections on the road to psychopathy.

    abstract::Psychopathy is strongly associated with serious criminal behaviour (for example, rape and murder) and recidivism. However, the biological basis of psychopathy remains poorly understood. Earlier studies suggested that dysfunction of the amygdala and/or orbitofrontal cortex (OFC) may underpin psychopathy. Nobody, howeve...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2009.40

    authors: Craig MC,Catani M,Deeley Q,Latham R,Daly E,Kanaan R,Picchioni M,McGuire PK,Fahy T,Murphy DG

    更新日期:2009-10-01 00:00:00

  • Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci.

    abstract::Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2013.2

    authors: Børglum AD,Demontis D,Grove J,Pallesen J,Hollegaard MV,Pedersen CB,Hedemand A,Mattheisen M,GROUP investigators10.,Uitterlinden A,Nyegaard M,Ørntoft T,Wiuf C,Didriksen M,Nordentoft M,Nöthen MM,Rietschel M,Ophoff RA,Cic

    更新日期:2014-03-01 00:00:00

  • Candidate genes, pathways and mechanisms for bipolar (manic-depressive) and related disorders: an expanded convergent functional genomics approach.

    abstract::Identifying genes for bipolar mood disorders through classic genetics has proven difficult. Here, we present a comprehensive convergent approach that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a stimulant--methamphetamine, and a mood sta...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/sj.mp.4001547

    authors: Ogden CA,Rich ME,Schork NJ,Paulus MP,Geyer MA,Lohr JB,Kuczenski R,Niculescu AB

    更新日期:2004-11-01 00:00:00

  • Thyroid hormone influences brain gene expression programs and behaviors in later generations by altering germ line epigenetic information.

    abstract::Genetic factors do not fully account for the relatively high heritability of neurodevelopmental conditions, suggesting that non-genetic heritable factors contribute to their etiology. To evaluate the potential contribution of aberrant thyroid hormone status to the epigenetic inheritance of neurological phenotypes, we ...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/s41380-018-0281-4

    authors: Martinez ME,Duarte CW,Stohn JP,Karaczyn A,Wu Z,DeMambro VE,Hernandez A

    更新日期:2020-05-01 00:00:00

  • What makes a drug a primary mood stabilizer?

    abstract::The term 'mood stabilizer' has been applied to a number of medications for the treatment of patients with bipolar disorder. The operational definition of the properties of a mood-stabilizing medication has varied according to the properties of specific medications and the clinical characteristics of the illness. Rando...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章,评审

    doi:10.1038/sj.mp.4001013

    authors: Keck PE Jr,McElroy SL,Richtand N,Tohen M

    更新日期:2002-01-01 00:00:00

  • The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.

    abstract::Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulatio...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2015.104

    authors: Sakae DY,Marti F,Lecca S,Vorspan F,Martín-García E,Morel LJ,Henrion A,Gutiérrez-Cuesta J,Besnard A,Heck N,Herzog E,Bolte S,Prado VF,Prado MA,Bellivier F,Eap CB,Crettol S,Vanhoutte P,Caboche J,Gratton A,Moquin L,

    更新日期:2015-11-01 00:00:00

  • Additional evidence for an association between the dopamine D4 receptor (D4DR) exon III repeat polymorphism and the human personality trait of Novelty Seeking.

    abstract::The long alleles (> or =6 repeats) of the dopamine D4 dopamine receptor exon III polymorphism have been linked in some, but not all, studies to Novelty Seeking (NS), one of four personality traits defined by Cloninger's tridimensional personality questionnarie (TPQ). In order to further examine the robustness of our o...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/sj.mp.4000333

    authors: Ebstein RP,Nemanov L,Klotz I,Gritsenko I,Belmaker RH

    更新日期:1997-10-01 00:00:00

  • The protocadherin 17 gene affects cognition, personality, amygdala structure and function, synapse development and risk of major mood disorders.

    abstract::Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) rev...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章,meta分析

    doi:10.1038/mp.2016.231

    authors: Chang H,Hoshina N,Zhang C,Ma Y,Cao H,Wang Y,Wu DD,Bergen SE,Landén M,Hultman CM,Preisig M,Kutalik Z,Castelao E,Grigoroiu-Serbanescu M,Forstner AJ,Strohmaier J,Hecker J,Schulze TG,Müller-Myhsok B,Reif A,Mitchell PB

    更新日期:2018-02-01 00:00:00

  • Epi-inositol regulates expression of the yeast INO1 gene encoding inositol-1-P synthase.

    abstract::Myo-inositol exerts behavioral effects in animal models of psychiatric disorders and is effective in clinical trials in psychiatric patients. Interestingly, epi-inositol exerts behavioral effects similar to myo-inositol, even though epi-inositol is not a substrate for synthesis of phosphatidylinositol. We postulated t...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/sj.mp.4000965

    authors: Shaldubina A,Ju S,Vaden DL,Ding D,Belmaker RH,Greenberg ML

    更新日期:2002-01-01 00:00:00

  • Presenilin 1 phosphorylation regulates amyloid-β degradation by microglia.

    abstract::Amyloid-β peptide (Aβ) accumulation in the brain is a hallmark of Alzheimer's Disease. An important mechanism of Aβ clearance in the brain is uptake and degradation by microglia. Presenilin 1 (PS1) is the catalytic subunit of γ-secretase, an enzyme complex responsible for the maturation of multiple substrates, such as...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/s41380-020-0856-8

    authors: Ledo JH,Liebmann T,Zhang R,Chang JC,Azevedo EP,Wong E,Silva HM,Troyanskaya OG,Bustos V,Greengard P

    更新日期:2020-08-13 00:00:00

  • Antidepressant efficacy of a selective organic cation transporter blocker in a mouse model of depression.

    abstract::Current antidepressants act principally by blocking monoamine reuptake by high-affinity transporters in the brain. However, these antidepressants show important shortcomings such as slow action onset and limited efficacy in nearly a third of patients with major depression disorder. Here, we report the development of a...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/s41380-019-0548-4

    authors: Orrico-Sanchez A,Chausset-Boissarie L,Alves de Sousa R,Coutens B,Rezai Amin S,Vialou V,Louis F,Hessani A,Dansette PM,Zornoza T,Gruszczynski C,Giros B,Guiard BP,Acher F,Pietrancosta N,Gautron S

    更新日期:2020-06-01 00:00:00

  • Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study.

    abstract::Endocannabinoids and their attending cannabinoid type 1 (CB1) receptor have been implicated in animal models of post-traumatic stress disorder (PTSD). However, their specific role has not been studied in people with PTSD. Herein, we present an in vivo imaging study using positron emission tomography (PET) and the CB1-...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2013.61

    authors: Neumeister A,Normandin MD,Pietrzak RH,Piomelli D,Zheng MQ,Gujarro-Anton A,Potenza MN,Bailey CR,Lin SF,Najafzadeh S,Ropchan J,Henry S,Corsi-Travali S,Carson RE,Huang Y

    更新日期:2013-09-01 00:00:00

  • Oligodendrocyte lineage cells and depression.

    abstract::Depression is a common mental illness, affecting more than 300 million people worldwide. Decades of investigation have yielded symptomatic therapies for this disabling condition but have not led to a consensus about its pathogenesis. There are data to support several different theories of causation, including the mono...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章,评审

    doi:10.1038/s41380-020-00930-0

    authors: Zhou B,Zhu Z,Ransom BR,Tong X

    更新日期:2021-01-01 00:00:00