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1.
Julie A. Harris Akihiko Koyama Sumihiro Maeda Kaitlyn Ho Nino Devidze Dena B. Dubal Gui-Qiu Yu Eliezer Masliah Lennart Mucke 《PloS one》2012,7(9)
Accumulation of hyperphosphorylated tau in the entorhinal cortex (EC) is one of the earliest pathological hallmarks in patients with Alzheimer’s disease (AD). It can occur before significant Aβ deposition and appears to “spread” into anatomically connected brain regions. To determine whether this early-stage pathology is sufficient to cause disease progression and cognitive decline in experimental models, we overexpressed mutant human tau (hTauP301L) predominantly in layer II/III neurons of the mouse EC. Cognitive functions remained normal in mice at 4, 8, 12 and 16 months of age, despite early and extensive tau accumulation in the EC. Perforant path (PP) axon terminals within the dentate gyrus (DG) contained abnormal conformations of tau even in young EC-hTau mice, and phosphorylated tau increased with age in both the EC and PP. In old mice, ultrastructural alterations in presynaptic terminals were observed at PP-to-granule cell synapses. Phosphorylated tau was more abundant in presynaptic than postsynaptic elements. Human and pathological tau was also detected within hippocampal neurons of this mouse model. Thus, hTauP301L accumulation predominantly in the EC and related presynaptic pathology in hippocampal circuits was not sufficient to cause robust cognitive deficits within the age range analyzed here. 相似文献
2.
James M. Mason Nita N. Scobie Akihiko H. Yamamoto 《Molecular & general genetics : MGG》1989,215(2):190-199
Summary The mutagen-sensitive mutant mus(1)104
D1
of Drosophila melanogaster maps to a position on the X chromosome very close to the meiotic mutant mei-41
D5
. Both mutants have been characterized as mutagen-sensitive and defective in post-replication repair. In the present report we show by complementation studies that mus(1)104 and mus(1)103 are allelic with mei-41. In addition, two reported alleles of mus(1)104 lie between the mei-41 alleles A10 and D5. The size of the mei-41 locus is estimated to be about 0.1 centimorgans (cM). Because several alleles of mei-41 have been shown to reduce recombination and increase meiotic chromosome loss and nondisjunction, mus(1)104
D1
females were examined for defects in meiosis. Although there was no evidence for reduced recombination on the second chromosome in homozygous mus(1)104
D1
females, heterozygous mus(1)104
D1
/mei-41
>D5
and mus(1)104
D1
/deficiency females showed reduced levels of recombination. However, there was no evidence of an increase in nondijunction in these females.We dedicate this article to the memory of Larry Sandler, who passed away suddenly on February 7, 1987 相似文献
3.
CBP2 protein promotes in vitro excision of a yeast mitochondrial group I intron. 总被引:12,自引:3,他引:9 下载免费PDF全文
The terminal intron (bI2) of the yeast mitochondrial cytochrome b gene is a group I intron capable of self-splicing in vitro at high concentrations of Mg2+. Excision of bI2 in vivo, however, requires a protein encoded by the nuclear gene CBP2. The CBP2 protein has been partially purified from wild-type yeast mitochondria and shown to promote splicing at physiological concentrations of Mg2+. The self-splicing and protein-dependent splicing reactions utilized a guanosine nucleoside cofactor, the hallmark of group I intron self-splicing reactions. Furthermore, mutations that abolished the autocatalytic activity of bI2 also blocked protein-dependent splicing. These results indicated that protein-dependent excision of bI2 is an RNA-catalyzed process involving the same two-step transesterification mechanism responsible for self-splicing of group I introns. We propose that the CBP2 protein binds to the bI2 precursor, thereby stabilizing the catalytically active structure of the RNA. The same or a similar RNA structure is probably induced by high concentrations of Mg2+ in the absence of protein. Binding of the CBP2 protein to the unspliced precursor was supported by the observation that the protein-dependent reaction was saturable by the wild-type precursor. Protein-dependent splicing was competitively inhibited by excised bI2 and by a splicing-defective precursor with a mutation in the 5' exon near the splice site but not by a splicing-defective precursor with a mutation in the core structure. Binding of the CBP2 protein to the precursor RNA had an effect on the 5' splice site helix, as evidenced by suppression of the interaction of an exogenous dinucleotide with the internal guide sequence. 相似文献
4.
Cloning and sequence analysis of a cDNA encoding the Rieske iron-sulfur protein of rat mitochondrial cytochrome bc1 complex 总被引:2,自引:0,他引:2
M Nishikimi Y Hosokawa H Toda H Suzuki T Ozawa 《Biochemical and biophysical research communications》1989,159(1):19-25
We have isolated a cDNA clone for the Rieske iron-sulfur protein of rat cytochrome bc1 complex, by screening a rat liver cDNA expression library using antiserum directed against the corresponding protein of bovine. The amino acid sequence deduced from the nucleotide sequence of the cDNA indicated that the mature polypeptide of the rat protein consists of 196 amino acid residues with a molecular weight of 21,465, and that it is formed as a precursor with an amino-terminal extension. Northern blot analysis indicated that rat liver possibly contains different sizes of mRNAs for the Rieske iron-sulfur protein, and Southern blot analysis demonstrated that rats and mice possess a single gene for this protein. 相似文献
5.
Summary Biosynthesis and processing of the protective protein for -galactosidase in normal and galactosialidosis fibroblasts were investigated using specific antiserum preparations. A 45-kd precursor was processed to a mature 30-kd protein in normal fibroblasts. The mature protective protein was not detected in any of the twelve galactosialidosis fibroblast strains examined in this study. The precursor was not detected in two cases and in the others was of heterogeneous molecular weight, i.e., normal, abnormally low, or abnormally high. These molecular abnormalities were not correlated with clinical manifestations of the patients. 相似文献
6.
Cloning and sequencing of a cDNA for human mitochondrial ubiquinone-binding protein of complex III 总被引:1,自引:0,他引:1
H Suzuki Y Hosokawa H Toda M Nishikimi T Ozawa 《Biochemical and biophysical research communications》1988,156(2):987-994
The ubiquinone-binding protein (QP-C) is a nuclear-encoded component of ubiquinol-cytochrome c oxidoreductase in the mitochondrial respiratory chain and plays an important role in electron transfer as a ubiquinone-QP-C complex. We obtained a partial cDNA for rat liver QP-C by screening a lambda gt11 rat liver cDNA library using antiserum directed against bovine heart QP-C. Using this cDNA as a probe, a cDNA clone was isolated from a human fibroblast cDNA library by colony hybridization. The total length of the cloned cDNA was 518 base pairs with an open reading frame of 333 base pairs. The 111-amino acid sequence deduced from the nucleotide sequence of the cDNA is 85% homologous to that of bovine QP-C and contains only a single additional amino-terminal methionine. This implies that the human QP-C is synthesized without a presequence which is required for import of most nuclear-encoded mitochondrial proteins into mitochondria. 相似文献
7.
Maternal inheritance of deleted mitochondrial DNA in a family with mitochondrial myopathy 总被引:17,自引:0,他引:17
T Ozawa M Yoneda M Tanaka K Ohno W Sato H Suzuki M Nishikimi M Yamamoto I Nonaka S Horai 《Biochemical and biophysical research communications》1988,154(3):1240-1247
Skeletal muscles from a mother and her daughter both with chronic progressive ophthalmoplegia were analyzed. Histological and biochemical analyses of their muscle samples showed typical features of this type of mitochondrial myopathy. Southern blot analysis revealed that, in both patients, there were two species of mitochondrial DNA (mtDNA): normal one and partially deleted one. The sizes of the deletion were different; the mutant mtDNAs from the mother and the daughter had about 2.5- and 5-kilobase deletions, respectively. The two mutant mtDNAs shared a common deleted region of 1.2-kilobase. However, both the start and the end of deletion were different between them, implying a novel mode of inheritance. This is the first report that the mutant mtDNA is responsible for the maternal inheritance of a human disease. 相似文献
8.
Humans, other primates, and guinea pigs are missing an enzyme L-gulono-gamma-lactone oxidase which catalyzes the last step of L-ascorbic acid biosynthesis. We have recently isolated a cDNA encoding this enzyme of the rat (T. Koshizaka, M. Nishikimi, T. Ozawa, and K. Yagi (1988) J. Biol. Chem. 263, 1619-1621). Northern blot hybridization using this cDNA as a probe demonstrated that guinea pigs lack mRNA for L-gulono-gamma-lactone oxidase. Nevertheless, existence of a DNA sequence related to this enzyme in the genome of this animal was shown by Southern blot hybridization. The human genome was also found to contain a sequence that is hybridizable with the cDNA probe; however, the degree of hybridization was less than those of hybridization with the L-gulono-gamma-lactone oxidase genes of animals possessing the enzyme, suggesting that the human L-gulono-gamma-lactone oxidase gene has diverged more rapidly than the genes of L-ascorbic acid-synthesizing species. This hypothesis was confirmed by comparison of a partial nucleotide sequence of the human gene with that of the rat one. The L-gulono-gamma-lactone oxidase-related sequences in the guinea pig and human genomes may represent the remnants of the gene of the enzyme that were once active but became nonfunctional during the course of evolution. 相似文献
9.
M Tanaka M Nishikimi H Suzuki T Ozawa M Nishizawa K Tanaka T Miyatake 《Biochemical and biophysical research communications》1986,140(1):88-93
The heart mitochondria isolated from a patient with hypertrophic cardiomyopathy associated with mitochondrial encephalomyopathy were analyzed by immunoblotting using specific antibody against each of the purified mitochondrial energy transducing complexes from beef heart. Subunits of NADH-ubiquinone oxidoreductase (Complex I) were markedly decreased and those of cytochrome c oxidase (Complex IV) were decreased to some extent, but the deficiency of any of these subunits was only partial. On the other hand, the contents of subunits of ubiquinol-cytochrome c oxidoreductase (Complex III) were normal. These results suggest that the decreased levels of some of the Complex I subunits might be the primary cause of disorder in this patient. 相似文献
10.
Reconstitution and poly(ADP-ribosyl)ation of proteolytically fragmented poly(ADP-ribose) synthetase 总被引:7,自引:0,他引:7
I Kameshita M Matsuda M Nishikimi H Ushiro Y Shizuta 《The Journal of biological chemistry》1986,261(8):3863-3868
Calf thymus poly(ADP-ribose) synthetase (Mr = 120,000) is cleaved with papain into two fragments of M(r) = 74,000 and 46,000 and also split with chymotrypsin into two fragments of M(r) = 66,000 and 54,000. Each fragment purified to homogeneity is enzymatically inactive, but combined incubation of the 74,000 and 46,000 fragments in the presence of DNA restored 20% of the enzyme activity. In contrast, combined incubation of the 66,000 and 54,000 fragments does not restore any enzyme activity. In the former incubation, autopoly(ADP-ribosyl)ation reaction occurs exclusively on the 74,000 fragment. When each fragment is incubated with [adenine-U-14C]NAD in the presence of DNA and a catalytic amount of the native enzyme, poly(ADP-ribosyl)action occurs in the overlapped portion (22,000) of the 66,000 fragment and the 74,000 fragment. Nevertheless, the purified 22,000 fragment is a poor acceptor for poly(ADP-ribosyl)ation. The degree of poly(ADP-ribosyl)ation of the proteolytic fragments is significantly reduced by increasing NaCl concentration, probably due to the lack of the interaction between the enzyme fragments and DNA. These results, taken together, indicate that DNA is indispensable for the reconstitution of the catalytic activity as well as the poly(ADP-ribosyl)ation of the fragmented enzyme. 相似文献