Altered subcellular localization of ornithine decarboxylase in Alzheimer’s disease brain

Karolinska Institutet, Neurotec, Section of Experimental Geriatrics, Novum, 141 86 Stockholm, Sweden.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 07/2006; 344(2):640-6. DOI: 10.1016/j.bbrc.2006.03.191
Source: PubMed


The amyloid precursor protein can through ligand-mimicking induce expression of ornithine decarboxylase (ODC), the initial and rate-limiting enzyme in polyamine biosynthesis. We report here the regional distribution and cellular localization of ODC immunoreactivity in Alzheimer's disease (AD) brains. In frontal cortex and hippocampus of control cases, the most pronounced ODC immunoreactivity was found in the nucleus. In possible and definite AD the immunoreactivity had shifted to the cytoplasm. In cerebellum of control cases, ODC staining was found in a small portion of Purkinje cells, mostly in the nucleus. In AD, both possible and definite, the number of stained Purkinje cells increased significantly and immunoreactivity was shifted to the cytoplasm, even though it was still prominent in the nucleus. In conclusion, our study reveals an early shift of the ODC immunoreactivity in AD from the nuclear compartment towards the cytoplasm.

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    • "Interestingly, polyamines are involved in the maintenance of adult neural stem cells [32] and display protective effects in neurodegenerative models [33] [34]. The significance of this hypothesis is reinforced by the fact that neuronal expression of ODC increases in proportion to the disease stage – indicating that the urea cycle may play a role in the AD process [35]. "
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    ABSTRACT: Since previous observations indicated that the urea cycle may have a role in the Alzheimer's disease (AD) process, we set out to quantify the expression of each gene involved in the urea cycle in control and AD brains and establish whether these genes could be genetic determinants of AD. We first confirmed that all the urea cycle enzyme genes are expressed in the AD brain. The expression of arginase 2 was greater in the AD brain than in the control brain. The presence of the rare arginase 2 allele rs742869 was associated with an increase in the risk of AD in men and with an earlier age-at-onset for both genders. None of the other genes in the pathway appeared to be differentially expressed in the AD brain or act as genetic determinants of the disease.
    Full-text · Article · Jan 2010 · Journal of Alzheimer's disease: JAD
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    • "However, our data shows a slight increase in the variation of gene expression between the cerebellum of AD subjects and that of the controls. This may be an indication that, although the cerebellum appears relatively unaffected by AD, some cerebellar pathology is present as previously described in the literature [28-30]. Interestingly, the observed range of expression of the genes in both the cerebellum and the medial temporal gyrus of the control subjects is generally much smaller than the range of expression of the same genes in the disease subjects. "
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    ABSTRACT: Studies of gene expression in post mortem human brain can contribute to understanding of the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Quantitative real-time PCR (RT qPCR) is often used to analyse gene expression. The validity of results obtained using RT qPCR is reliant on accurate data normalization. Reference genes are generally used to normalize RT qPCR data. Given that expression of some commonly used reference genes is altered in certain conditions, this study aimed to establish which reference genes were stably expressed in post mortem brain tissue from individuals with AD, PD or DLB. The present study investigated the expression stability of 8 candidate reference genes, (ubiquitin C [UBC], tyrosine-3-monooxygenase [YWHAZ], RNA polymerase II polypeptide [RP II], hydroxymethylbilane synthase [HMBS], TATA box binding protein [TBP], beta-2-microglobulin [B2M], glyceraldehyde-3-phosphate dehydrogenase [GAPDH], and succinate dehydrogenase complex-subunit A, [SDHA]) in cerebellum and medial temporal gyrus of 6 AD, 6 PD, 6 DLB subjects, along with 5 matched controls using RT qPCR (TaqMan(R) Gene Expression Assays). Gene expression stability was analysed using geNorm to rank the candidate genes in order of decreasing stability in each disease group. The optimal number of genes recommended for accurate data normalization in each disease state was determined by pairwise variation analysis. This study identified validated sets of mRNAs which would be appropriate for the normalization of RT qPCR data when studying gene expression in brain tissue of AD, PD, DLB and control subjects.
    Full-text · Article · Feb 2008 · BMC Molecular Biology
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    ABSTRACT: Ornithine decarboxylase (ODC) regulates the synthesis of polyamines which are involved in many cellular functions e.g. proliferation and differentiation. Due to its critical role, ODC is a tightly regulated enzyme by antizymes and antizyme inhibitors. If the regulation fails, the activity of ODC increases and may lead to malignant transformation of a cell. Increased ODC activity is found in many common cancers, including colon, prostate, and breast cancer. In a transformed cell, dynamics of the actin cytoskeleton is disturbed. A small G-protein, RhoA regulates organization of the cytoskeleton, and its overactivity increases malignant potential of the cell. The present results indicate that covalent attachment of polyamines by transglutaminase is a physiological means of regulating the activity of RhoA. The translocation of RhoA to the plasma membrane, where it exerts its activity is dependent on the presence of catalytically active ODC. As the overactivity of ODC and RhoA are implicated in cell transformation, the results provide a mechanistic explanation of the interrelationship between the polyamine metabolism and the reorganization of the actin cytoskeleton occurring in cancer cells. ODC and polyamines have also an important role in the function of central nervous system. They participate in the regulation of brain morphogenesis in embryos. In adult nervous tissue, polyamines regulate K+ and glutamate channels. K+ inward rectifying channels control membrane potentials and NMDA-type glutamate receptors (NMDAR) regulate synaptic plasticity. High ODC activity and polyamine levels are considered important in the development of ischemic brain damage and they are implicated in the pathogenesis of Alzheimer s disease (AD). A homolog of ODC was cloned from a human brain cDNA library, and several alternatively spliced variants were detected in human brain and testis. The novel protein was nevertheless devoid of ODC catalytic activity. It was subsequently found to be a novel inductor of ODC activity and polyamine synthesis, called antizyme inhibitor 2 (AZIN2). The accumulation of AZIN2 in vesicle-like formations along the axons and beneath the plasma membrane of neurons as well as in steroid hormone producing Leydig cells and luteal cells of the gonads implies that AZIN2 plays a role in secretion and vesicle trafficking. An accumulation of AZIN2 was detected also in specimens of AD brains. This increased expression of AZIN2 was specific for AD and was not found in brains with other neurodegenerative diseases including CADASIL or dementia with Lewy bodies. Polyamiinit ovat pieniä, sähköisesti varautuneita molekyylejä, joita on runsaasti soluissa, pääosin sitoutuneena perintöainekseen. Polyamiineja saadaan ruuasta, mutta pääosan solu valmistaa itse. Ne ovat välttämättömiä monen solun keskeisen toiminnan, kuten jakautumisen ja erilaistumisen kannalta. Ornitiinidekarboksylaasi (ODC) säätelee polyamiinien tuotantoa solussa. Keskeisen roolinsa vuoksi ODC on erittäin tarkasti säädelty entsyymi, ja säätelyn pettäessä ja ODC:n aktiivisuuden noustessa solu saattaa transformoitua eli muuttua pahanlaatuiseksi. ODC-aktiivisuuden kasvu on nähtävissä monissa syövissä, kuten rinta- eturauhas- ja paksusuolen syövissä. Syöpähoitoja, joissa säädellään ODC:n aktiivisuutta ja polyamiinien pitoisuutta on pyritty kehittämään, mutta tulokset ovat olleet heikkoja johtuen ODC:n monimutkaisesta ja osittain vielä tuntemattomasta säätelystä. Väitöskirjatutkimuksissani olen osoittanut molekulaarisen mekanismin, jolla ODC ja polyamiinit säätelevät solun aktiinitukirangan muovautumista ja vaikuttavat solun transformaatioon. Tutkimustuloksemme viittaavat siihen, että ODC säätelee pientä G-proteiinia, RhoA:ta, joka on aktiinitukirangan säätelijä, vaikuttamalla sen solunsisäiseen sijoittumiseen ja polyaminaatioon. Nämä interaktiot vaikuttavat solun jakautumissyklin etenemiseen ja solun transformaatioon. ODC:lla ja polyamiineilla on tärkeä rooli myös keskushermoston toiminnassa. Ne osallistuvat aivojen morfogeneesin säätelyyn ja toisaalta aikuisen aivoissa säätelevät eksitatorista glutamaattireseptoria, NMDAR:ia. NMDAR on keskeinen oppimisen ja muistin toiminnan kannalta, ja sillä epäillään olevan osallisuutta myös Alzheimerin taudin patogeneesissä. Myös ODC:n aktiivisuuden ja polyamiinien pitoisuuden tiedetään olevan koholla monissa keskushermoston patologisissa tiloissa, kuten aivoverenkiertohäiriöissä ja Alzheimerin taudissa. Olemme kuvanneet aivoista aiemmin tuntemattoman ODC:n säätelijän, antitsyymi-inhibiittori 2:n (AZIN2). Tulostemme mukaan AZIN2 sijoittuu samoihin soluihin NMDAR:n kanssa, ja sen määrä on ODC:n tavoin lisääntynyt Alzheimerin taudissa. AZIN2 ilmentyy myös kivesten ja munasarjojen sukupuolihormoneja tuottavissa soluissa viitaten toiminnalliseen rooliin solun hormonituotannossa tai erityksessä.
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