Ribosomal RNA in Alzheimer disease is oxidized by bound redox-active iron

被引:227
作者
Honda, K
Smith, MA
Zhu, XW
Baus, D
Merrick, WC
Tartakoff, AM
Hattier, T
Harris, PL
Siedlak, SL
Fujioka, H
Liu, Q
Moreira, PI
Miller, FP
Nunomura, A
Shimohama, S
Perry, G
机构
[1] Case Western Reserve Univ, Inst Pathol, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44106 USA
[3] Univ Coimbra, Ctr Neurosci & Cell Biol Coimbra, P-3004517 Coimbra, Portugal
[4] Asahikawa Med Coll, Dept Psychiat & Neurol, Asahikawa, Hokkaido 0788510, Japan
[5] Kyoto Univ, Grad Sch Med, Dept Neurol, Kyoto 6068507, Japan
关键词
D O I
10.1074/jbc.M500526200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Oxidative modification of cytoplasmic RNA in vulnerable neurons is an important, well documented feature of the pathophysiology of Alzheimer disease. Here we report that RNA-bound iron plays a pivotal role for RNA oxidation in vulnerable neurons in Alzheimer disease brain. The cytoplasm of hippocampal neurons showed significantly higher redox activity and iron(II) staining than age-matched controls. Notably, both were susceptible to RNase, suggesting a physical association of iron( II) with RNA. Ultrastructural analysis further suggested an endoplasmic reticulum association. Both rRNA and mRNA showed twice the iron binding as tRNA. rRNA, extremely abundant in neurons, was considered to provide the greatest number of iron binding sites among cytoplasmic RNA species. Interestingly, the difference of iron binding capacity disappeared after denaturation of RNA, suggesting that the higher order structure may contribute to the greater iron binding of rRNA. Reflecting the difference of iron binding capacity, oxidation of rRNA by the Fenton reaction formed 13 times more 8-hydroxyguanosine than tRNA. Consistent with in situ findings, ribosomes purified from Alzheimer hippocampus contained significantly higher levels of RNase-sensitive iron( II) and redox activity than control. Furthermore, only Alzheimer rRNA contains 8-hydroxyguanosine in reverse transcriptase-PCR. Addressing the biological significance of ribosome oxidation by redox-active iron, in vitro translation with oxidized ribosomes from rabbit reticulocyte showed a significant reduction of protein synthesis. In conclusion these results suggest that rRNA provides a binding site for redoxactive iron and serves as a redox center within the cytoplasm of vulnerable neurons in Alzheimer disease in advance of the appearance of morphological change indicating neurodegeneration.
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页码:20978 / 20986
页数:9
相关论文
共 52 条
[1]  
Alberts B., 1994, MOL BIOL CELL
[2]   Characterization of copper interactions with Alzheimer amyloid β peptides:: Identification of an attomolar-affinity copper binding site on amyloid β1-42 [J].
Atwood, CS ;
Scarpa, RC ;
Huang, XD ;
Moir, RD ;
Jones, WD ;
Fairlie, DP ;
Tanzi, RE ;
Bush, AI .
JOURNAL OF NEUROCHEMISTRY, 2000, 75 (03) :1219-1233
[3]   The complete atomic structure of the large ribosomal subunit at 2.4 Å resolution [J].
Ban, N ;
Nissen, P ;
Hansen, J ;
Moore, PB ;
Steitz, TA .
SCIENCE, 2000, 289 (5481) :905-920
[4]   Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice [J].
Bayer, TA ;
Schäfer, S ;
Simons, A ;
Kemmling, A ;
Kamer, T ;
Tepest, R ;
Eckert, A ;
Schüssel, K ;
Eikenberg, O ;
Sturchler-Pierrat, C ;
Abramowski, D ;
Staufenbiel, M ;
Multhaup, G .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (24) :14187-14192
[5]   Visualizing metal-ion-binding sites in group I introns by iron(II)-mediated Fenton reactions [J].
Berens, C ;
Streicher, B ;
Schroeder, R ;
Hillen, W .
CHEMISTRY & BIOLOGY, 1998, 5 (03) :163-175
[6]   Proteomic identification of oxidatively modified proteins in Alzheimer's disease brain. Part 1: Creatine kinase bb, glutamine synthase, and ubiquitin carboxy-terminal hydrolase L-1 [J].
Castegna, A ;
Aksenov, M ;
Aksenova, M ;
Thongboonkerd, V ;
Klein, JB ;
Pierce, WM ;
Booze, R ;
Markesbery, WR ;
Butterfield, DA .
FREE RADICAL BIOLOGY AND MEDICINE, 2002, 33 (04) :562-571
[7]   Metal-binding sites in the major groove of a large ribozyme domain [J].
Cate, JH ;
Doudna, JA .
STRUCTURE, 1996, 4 (10) :1221-1229
[8]   A strategy for immunohistochemical signal enhancement by end-product amplification [J].
Chen, BX ;
Szabolcs, MJ ;
Matsushima, AY ;
Erlanger, BF .
JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY, 1996, 44 (08) :819-824
[9]   Formation of the oxidative damage marker 8-hydroxy-2′-deoxyguanosine from the nucleoside 2′-deoxyguanosine:: parameter studies and evidence of Fe(II) binding [J].
Colwell, BA ;
Morris, DL .
JOURNAL OF INORGANIC BIOCHEMISTRY, 2003, 94 (1-2) :100-105
[10]   REGIONAL DISTRIBUTION OF IRON AND IRON-REGULATORY PROTEINS IN THE BRAIN IN AGING AND ALZHEIMERS-DISEASE [J].
CONNOR, JR ;
SNYDER, BS ;
BEARD, JL ;
FINE, RE ;
MUFSON, EJ .
JOURNAL OF NEUROSCIENCE RESEARCH, 1992, 31 (02) :327-335