研究者詳細 - 小野寺　理

論文 - 小野寺　理

分割表示 492 件中 381 - 400 件目／全件表示 >>

Churg-Strauss syndrome and the leukotriene receptor antagonist pranlukast 査読

J Shimbo, O Onodera, K Tanaka, S Tsuji

CLINICAL RHEUMATOLOGY 24 ( 6 ) 661 - 662 2005年12月

記述言語：英語出版者・発行元：SPRINGER

The authors studied eight cases of Churg-Strauss syndrome (CSS) associated with the use of pranlukast, a common cysteinyl leukotriene receptor antagonist (LTRA) in Japan. The patients who received pranlukast showed significantly increased peripheral blood eosinophil count, neurological disability scores, and poor responses to corticosteroid in comparison with those patients not receiving pranlukast. We suggest that preceding administration of pranlukast aggravates clinical presentations of CSS.

DOI： 10.1007/s10067-004-1035-z

Selective silencing of a mutant transthyretin allele by small interfering RNAs 査読

T Kurosawa, S Igarashi, M Nishizawa, O Onodera

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 337 ( 3 ) 1012 - 1018 2005年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

Familial amyloidotic polyneuropathy (FAP) is a hereditary systemic amyloidosis caused by dominantly acting missense mutations in the gene encoding transthyretin (TTR). The most common mutant TTR is of the Va130Met type, which results from a point mutation. Because the major constituent of amyloid fibrils is mutant TTR, agents that selectively suppress mutant TTR expression could be powerful therapeutic tools. This study has been performed to evaluate the use of small interfering RNAs (siRNAs) for the selective silencing of mutant Va130Met TTR in cell culture systems. We have identified an siRNA that specifically inhibits mutant, but not wild-type, TTR expression even in cells expressing both alleles. Thus, this siRNA-based approach may have potential for the gene therapy of FAR (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2005.09.142

DNA repair and neurodegeneration 査読

Osamu Onodera

Clinical Neurology 45 ( 11 ) 979 - 981 2005年11月

記述言語：日本語掲載種別：研究論文（国際会議プロシーディングス）

Early onset ataxia with hypoalbuminemia (AOA1/EAOH) patients begin with ocular motor apraxia and cerebellar ataxia in childhood, and then develop axonal peripheral neuropathy and hypoalbuminemia. We and others identified 'aprataxin (APTX) ' as the causative gene for AOA1/EAOH. APTX binds to XRCC1, which is the scaffold protein for BER machinery, and has a HIT-motif, which is supposed to have hydrolase activity on nucleotide. These properties suggest that APTX acts on DNA during single strand DNA break. The 3′-termini of single strand DNA break must be hydroxylated to allow DNA polymerase or ligase to repair
however, ordinary the 3′-termini is modified by phosphate or others. These unsuitable ends have to be removed to repair. To investigate whether the APTX works on DNA and remove the unsuitable 3′-end, we incubated recombinant human APTX with variable oligonucleotide. We show that APTX has bidirectional exonuclease activity and 3′-phosphatase activity. These results indicate that APTX might modify the phosphorylated 3′-end in a single strand DNA break. To date several diseases have been identified as caused by an impairment of quality control system of DNA/ RNA. The impairment of quality control system of DNA/RNA is a new pathway for neuronal degeneration.

Natural history of X-linked adrenoleukodystrophy in Japan 査読

Y Suzuki, Y Takemoto, N Shimozawa, T Imanaka, S Kato, H Furuya, M Kaga, K Kato, N Hashimoto, O Onodera, S Tsuji

BRAIN & DEVELOPMENT 27 ( 5 ) 353 - 357 2005年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

The natural history of X-linked adrenoleukodystrophy (ALD) was investigated, using a nation-wide retrospective study based on a questionnaire survey. The data on 145 patients, including 46 patients with the childhood cerebral form, 39 with adrenomyeloneuropathy (AMN), 33 with the adult cerebral form, 14 with the adolescent form and 13 with the olivo-ponto-cerebellar (OPC) form, were analyzed. Initial symptoms of the childhood cerebral form were intellectual (n=16) and visual (n = 11) disturbances, whereas those of AMN were gait (n = 37) and sensory (n = 3) disturbances; the adult cerebral form, psychic (n= 19) and gait (n = 11)disturbances; the adolescent form, visual n = 5) and gait (n = 4) disturbances; and the OPC form, gait (n = 9) disturbance. Patients with onset under the age of 8 years progressed more rapidly than those over 8 years old. Visual, hearing, gait and swallowing disturbances progressed more slowly in the older group. About half of AMN patients showed cerebral involvement about 10 years after onset. Patients with the OPC form also showed a similar progression. A Kaplan-Meier plot clarified the characteristic pattern of progression of neurological symptoms in each phenotype. These finding will improve the understanding of the natural history of X-linked ALD and will provide a basis for the evaluation of specific treatment for X-linked ALD. (c) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2004.09.008

Age associated axonal features in HNPP with 17p11.2 deletion in Japan 査読

H Koike, M Hirayama, M Yamamoto, H Ito, N Hattori, F Umehara, K Arimura, S Ikeda, Y Ando, M Nakazato, R Kaji, K Hayasaka, M Nakagawa, S Sakoda, K Matsumura, O Onodera, M Baba, H Yasuda, T Saito, J Kira, K Nakashima, N Oka, G Sobue

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 76 ( 8 ) 1109 - 1114 2005年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：B M J PUBLISHING GROUP

Objective: To clarify age related changes in the clinicopathological features of hereditary neuropathy with liability to pressure palsy ( HNPP) in Japanese patients with deletion of 17p11.2, particularly concerning axonal abnormalities.
Methods: Forty eight proband patients from 48 HNPP families were assessed as to clinical, electrophysiological, and histopathological features, including age associated changes beyond those in controls.
Results: Motor conduction studies showed age associated deterioration of compound muscle action potentials in nerves vulnerable to repetitive compression (median, ulnar, and peroneal nerves), but not in others such as the tibial nerve. Sensory conduction studies revealed more profound reduction of action potentials than motor studies with little age related change. Large myelinated fibre loss was seen in the sural nerve irrespective of age at examination.
Conclusions: Irreversible axonal damage may occur at entrapment sites in motor nerves in HNPP patients, progressing with aging. Sensory nerves may show more profound axonal abnormality, but without age association. The electrophysiological features of HNPP are presumed to be a mixture of abnormalities occurring from early in life and acquired features caused by repetitive insults at entrapment sites. Unlike Charcot-Marie-Tooth disease type 1A, age associated axonal damage may not occur unless the nerves are subjected to compression.

DOI： 10.1136/jnnp.2004.048140

A late-onset case of oculopharyngeal muscular dystrophy carrying a (GCG) 8 repeat expansion in the PAPBN1 gene 査読

Takayoshi Tokutake, Takeshi Ikeuchi, Keiko Tanaka, Osamu Onodera, Masatoyo Nishizawa

Clinical Neurology 45 ( 6 ) 437 - 440 2005年6月

記述言語：日本語掲載種別：研究論文（学術雑誌）

We report a sporadic case of a female patient with oculopharyngeal muscular dystrophy (OPMD). Her father died at age 86 and mother at age 74. There was no familial occurrence of the disease. The patient initially developed a nasal voice at age 66. Neurological examinations on admission at age 72 revealed bilateral ptosis, a limitation of ocular movement without diplopia, dysphagia, and proximal muscle weakness. Serum creatine kinase level was slightly increased. Biopsied muscle specimens showed variation in fiber size as well as the occasional presence of rimmed vacuoles. On the basis of these clinical and laboratory findings, we suspected a diagnosis of OPMD, although a family history was absent. To confirm the diagnosis of OPMD, we performed a gene analysis for poly A binding protein, nuclear 1 (PABPN1
PABP2), which revealed a mild expansion of GCG repeat (8 repeats) as a heterozygous state. Clinical features of the patient were consistent with those in a previous literature reporting that patients carrying (GCG) 8 repeat as a heterozygous state show a relatively late onset and a mild phenotype. The case of this patient emphasizes the importance of the PABPN1 gene analysis for patients showing muscular weakness involving oculopharyngeal and proximal limb muscles even when a familial occurrence of the disease is not apparent.

Clinical and electrophysiologic correlates of IVIg responsiveness in CIDP 査読

M Iijima, M Yamamoto, M Hirayama, F Tanaka, M Katsuno, K Mori, H Koike, N Hattori, K Arimura, M Nakagawa, H Yoshikawa, K Hayasaka, O Onodera, M Baba, H Yasuda, T Saito, M Nakazato, K Nakashima, J Kira, R Kaji, N Oka, G Sobue

NEUROLOGY 64 ( 8 ) 1471 - 1475 2005年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

To identify clinical and electrophysiologic features related to IV immunoglobulin (IVIg) responsiveness in chronic inflammatory demyelinating polyneuropathy ( CIDP), the authors conducted a multicenter study on 312 patients with CIDP ( 199 responders and 113 nonresponders). Muscle atrophy and decreased compound muscle action potential were pronounced in nonresponders of IVIg. Male gender, longer disease duration, and slow progression of symptoms were also associated with IVIg unresponsiveness. Features suggesting axonal dysfunction in peripheral nerves indicated IVIg unresponsiveness in CIDP.

DOI： 10.1212/01.WNL.0000158680.89323.F8

A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease 査読

A Ishikawa, YS Piao, A Miyashita, R Kuwano, O Onodera, H Ohtake, M Suzuki, M Nishizawa, H Takahashi

ANNALS OF NEUROLOGY 57 ( 3 ) 429 - 434 2005年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-LISS

We report early-onset parkinsonism and dementia of 18 years' duration in a 52-year-old man whose grandfather and father had suffered from a similar neurological disease. In this patient, we found neuronal loss in various brain regions including the substantia nigra and cerebral cortex, Lewy bodies, cotton wool plaques, corticospinal tract degeneration, cerebral amyloid angiopathy, and a novel three-base pair deletion in exon 12 of the presenilin-1 (PSEN1) gene. We considered that the mutant PSEN1 might play an important role in the pathogenetic process of both aggregation of a-synuclein into Lewy bodies and deposition of beta-amyloid into cotton wool plaques.

DOI： 10.1002/ana.20393

A pedigree of Charcot-Marie-Tooth disease type 4F (Periaxin mutation) 査読

Mitsuteru Shimohata, Kiyoshi Hirahara, Shuichi Igarashi, Kenju Hara, Kazuki Kijima, Osamu Onodera, Keiko Tanaka, Masatoyo Nishizawa, Shoji Tsuji, Kiyoshi Hayasaka

Clinical Neurology 45 ( 3 ) 221 - 225 2005年3月

記述言語：日本語掲載種別：研究論文（学術雑誌）

We report a 51-year-old man genetically diagnosed as Charcot-Marie-Tooth disease type 4F. The patient was the first child of healthy, consanguineous parents. He had two sisters and one of them showed similar but milder symptoms. He had gait disturbance since childhood. Then he noticed muscle weakness of his hands at the age of early forties, and more difficulties in gait at the age of late forties. On examination at age 51, he showed absence of all deep tendon reflexes, weakness of the hand and distal leg muscles, pes cavus and decreased sensitivity to touch and vibration in the lower extremities. Electrophysiological studies of the median nerve showed delayed motor nerve conduction velocity and undetectable sensory nerve action potentials. The histology of his sural nerve revealed moderate loss of large myelinated fibers and the diameters of residual fibers shifted to small shown as size-frequency histogram. Many fibers are thinly myelinated and some of the Schwann cells looked as wrapping around the myelinate fibers with their processes. On gene analyses, we identified an Arg 1070 Stop homozygous mutation in the Periaxin, known to be a causative gene for CMT type 4F. Based on these observations, we emphasized that broad genetic analyses are necessary for diagnosis of CMT disease, including so far unidentified mutations among the Japanese populations.

Sacsin-related autosomal recessive ataxia without prominent retinal myelinated fibers in Japan 査読

K Hara, O Onodera, M Endo, H Kondo, H Shiota, K Miki, N Tanimoto, T Kimura, M Nishizawa

MOVEMENT DISORDERS 20 ( 3 ) 380 - 382 2005年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-LISS

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) has been described in the Quebec region and in Tunisia. We report on two Japanese siblings with a new homozygous mutation (6543 del A) of the SACS gene. Compared with previously reported ARSACS patients, both of these patients had a unique phenotype characterized by dementia, ophthalmoplegia, and the absence of prominent retinal myelinated fibers. (c) 2004 Movement Disorder Society.

DOI： 10.1002/mds.20315

Polyglutamine represses cAMP-responsive-element-mediated transcription without aggregate formation 査読

T Takahashi, K Nozaki, S Tsuji, M Nishizawa, O Onodera

NEUROREPORT 16 ( 3 ) 295 - 299 2005年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

Transcriptional dysregulation, particularly cAMP-responsive-element-mediated transcriptional repression, has been implicated in expanded polyglutamine diseases. However, it has not been clarified whether this transcriptional repression is a cause or result of neurodegeneration. Furthermore, the association between aggregates of expanded polyglutamine stretches and transcriptional repression is not clear. We established isogenic cell lines with polyglutamine stretches, which also expressed d2EGFP under the control of cAMP-responsive elements. In this system, the polyglutamine stretch repressed cAMP-responsive-element-mediated transcription without the formation of macroscopic expanded polyglutamine aggregates. Furthermore, aggregate formation did not have an adverse effect on the repression of transcriptional activity. The results demonstrated that the repression of cAMP-responsive-element-mediated transcription is an early event caused by a soluble form of polyglutamine stretch. (c) 2005 Lippincott Williams T Wilkins.

DOI： 10.1097/00001756-200502280-00019

Evaluation of two patients with SCA2 with frontal lobe dysfunction using brain SPECT with three-dimensional stereotactic surface projections (3D-SSP) 査読

Takayoshi Shimohata, Yoko Matsuzawa, Koumei Tanaka, Osamu Onodera, Keiko Tanaka, Masatoyo Nishizawa

Clinical Neurology 45 ( 1 ) 22 - 26 2005年1月

記述言語：日本語掲載種別：研究論文（学術雑誌）

We evaluated the cognitive impairment of two patients with genetically confirmed spinocerebellar ataxia type 2 (SCA2). Neurological examination revealed ignorance of his illness and Gegenhalten phenomenon in patient 1, and emotional incontinence in patient 2. Although their mental status evaluated by HDS-R or Mini-Mental State Examination (MMSE) was almost normal, the results of WAIS-R and Wisconsin Card Sorting Test (WCST) revealed the existence of intellectual decline and executive dysfunction. 3D-SSP SPECT demonstrated distinct hypoperfusion in bilateral frontal lobes, whereas brain MRI revealed no apparent cerebral atrophy in both patients. These results raise the possibility that frontal lobe dysfunction was observed in the early stages of SCA2, and that 3D-SSP SPECT is useful for evaluating the involvement of frontal lobe dysfunction in SCA2.

The FHA domain of aprataxin interacts with the C-terminal region of XRCC1 査読

H Date, S Igarashi, Y Sano, T Takahashi, T Takahashi, H Takano, S Tsuji, M Nishizawa, O Onodera

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 325 ( 4 ) 1279 - 1285 2004年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

Aprataxin (APTX) is the causative gene product for early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH/AOA1). In our previous study, we found that APTX interacts with X-ray repair cross-complementing group 1 (XRCC1), a scaffold protein with an essential role in single-strand DNA break repair (SSBR). To further characterize the functions of APTX, we determined the domains of APTX and XRCC1 required for the interaction. We demonstrated that the 20 N-terminal amino acids of the FHA domain of APTX are important for its interaction with the C-terminal region (residues 492-574) of XRCC1. Moreover, we found that poly (ADP-ribose) polymerase-1 (PARP-1) is also co-immunoprecipitated with APTX. These findings suggest that APTX, together with XRCC1 and PARP-1, plays an essential role in SSBR. (C) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2004.10.162

Clinical spectrums of SCA 17 depend on length of CAA/CAG repeat units in the TBP gene. 査読

Toyoshima Y, Yamada M, Onodera O, Shimohata M, Inenaga C, Fujita N, Morita M, Tsuji S, Takahashi H

Annals of Neurology 56 163 - 164 2004年12月

beta-Synuclein gene alterations in dementia with Lewy bodies 査読

H Ohtake, P Limprasert, Y Fan, O Onodera, A Kakita, H Takahashi, LT Bonner, DW Tsuang, IVJ Murray, VMY Lee, JQ Trojanowski, A Ishikawa, J Idezuka, M Murata, T Toda, TD Bird, JB Leverenz, S Tsuji, AR La Spada

NEUROLOGY 63 ( 5 ) 805 - 811 2004年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

Objective: To determine whether mutations in the genes for alpha-synuclein or beta-synuclein are responsible for dementia with Lewy bodies ( DLB), a disorder closely related to Parkinson disease (PD). Methods: The authors ascertained 33 sporadic cases of DLB and 10 kindreds segregating DLB. DNA samples from the 43 index cases were screened for alterations in the genes for alpha-synuclein and beta-synuclein, as alpha-synuclein alterations cause PD and beta-synuclein may modulate alpha-synuclein aggregation and neurotoxicity. Results: Two amino acid alterations were identified in unrelated DLB index cases: a valine to methionine substitution at codon 70 (V70M) and a proline to histidine substitution at codon 123 (P123H), both in the beta-synuclein gene. These amino acid substitutions occur at conserved residues in highly conserved regions of the beta-synuclein protein. Screening of at least 660 chromosomes from control subjects matched to the patients' population groups failed to identify another V70M or P123H allele. Cosegregation analysis of an extended pedigree segregating the P123H beta-synuclein alteration suggested that it is a dominant trait with reduced penetrance or a risk factor polymorphism. Histopathology and immunohistochemistry analysis of index case brain sections revealed widespread Lewy body pathology and alpha-synuclein aggregation without evidence of beta-synuclein aggregation. Conclusion: Mutations in the beta-synuclein gene may predispose to DLB.

Quantitative evaluation of brainstem involvement in multiple system atrophy by diffusion-weighted MR imaging 査読

M Kanazawa, T Shimohata, K Terajima, O Onodera, K Tanaka, S Tsuji, K Okamoto, M Nishizawa

JOURNAL OF NEUROLOGY 251 ( 9 ) 1121 - 1124 2004年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：DR DIETRICH STEINKOPFF VERLAG

In multiple system atrophy (MSA), symptoms associated with dysfunctions of the brainstem and autonomic nervous system are important prognostic factors. We investigated brainstem involvement in 12 patients with MSA with predominant cerebellar symptoms (MSA-C) (mean age, 56.3 +/- 9.9 years, median disease duration, 3 years), and 11 controls (57.6 +/- 12.0 years) matched for age using diffusion-weighted MR imaging (DWI). We demonstrated that apparent diffusion coefficients (ADCs) in the pons and middle cerebellar peduncle of MSA-C patients are significantly higher than those of normal controls even though the patients are in the early stage of the disease. Furthermore, we demonstrated that increased ADC values correlated well with the disease duration. The current study demonstrated that DWI is a useful noninvasive method for the quantitative evaluation of the brainstem involvement in MSA-C patients.

DOI： 10.1007/s00415-004-0494-0

Five year follow up of a patient with spinal and bulbar muscular atrophy treated with leuprorelin 査読

T Shimohata, T Kimura, M Nishizawa, O Onodera, S Tsuji

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 75 ( 8 ) 1206 - 1207 2004年8月

Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5 査読

H Ohtake, T Shimohata, K Terajima, T Kimura, R Jo, R Kaseda, O Iizuka, M Takano, Y Akaiwa, H Goto, H Kobayashi, T Sugai, T Muratake, T Hosoki, T Shioiri, K Okamoto, O Onodera, K Tanaka, T Someya, T Nakada, S Tsuji

NEUROLOGY 62 ( 9 ) 1601 - 1603 2004年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

We report of a woman aged 52 years born to consanguineous parents and seeking treatment for progressive dementia and delusion. Neurologic examination revealed dementia and emotional instability, indifference, and confabulation. There was also mild spasticity of the bilateral lower limbs. MRI revealed diffuse white matter hyperintensity on T2-weighted images accompanied by hypointense areas on fluid-attenuated inversion recovery images. A homozygous missense mutation was identified in EIF2B5.

Disruption of the toxic conformation of the expanded polyglutamine stretch leads to suppression of aggregate formation and cytotoxicity 査読

HA Popiel, Y Nagai, O Onodera, T Inui, N Fujikake, Y Urade, WJ Strittmatter, Burke, JR, A Ichikawa, T Toda

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 317 ( 4 ) 1200 - 1206 2004年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

The polyglutamine (polyQ) diseases are a class of inherited neurodegenerative diseases including Huntington's disease, caused by the expansion of a polyQ stretch within each disease protein. This expansion is thought to cause a conformational change in the protein leading to aggregation of the protein, resulting in cytotoxicity. To analyze whether disrupting the toxic conformation of the polyQ protein can alter its aggregation propensity and cytotoxicity, we examined the effect of interruption of the expanded polyQ stretch by proline insertion, since prolines cause great alterations in protein conformation. Here, we show that insertion of prolines into the expanded polyQ stretch indeed disrupts its ordered secondary structure, leading to suppression of polyQ protein aggregation both in vitro and in cell culture, and reduction of cytotoxicity in correlation with the number of proline interruptions. Furthermore, we found that a short polyQ stretch with a proline interruption is able to inhibit aggregation of the expanded polyQ protein in trans. These results show that a gain in toxic conformation of the expanded polyQ protein is essential for aggregation and cytotoxicity, providing insight into establishing therapies against the polyQ diseases. (C) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2004.03.161

Aprataxin, a novel protein that protects against genotoxic stress 査読

N Gueven, OJ Becherel, AW Kijas, P Chen, O Howe, JH Rudolph, R Gatti, H Date, O Onodera, G Taucher-Scholz, MF Lavin

HUMAN MOLECULAR GENETICS 13 ( 10 ) 1081 - 1093 2004年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OXFORD UNIV PRESS

Ataxia-oculomotor apraxia (AOA1) is a neurological disorder with symptoms that overlap those of ataxia-telangiectasia, a syndrome characterized by abnormal responses to double-strand DNA breaks and genome instability. The gene mutated in AOA1, APTX, is predicted to code for a protein called aprataxin that contains domains of homology with proteins involved in DNA damage signalling and repair. We demonstrate that aprataxin is a nuclear protein, present in both the nucleoplasm and the nucleolus. Mutations in the APTX gene destabilize the aprataxin protein, and fusion constructs of enhanced green fluorescent protein and aprataxin, representing deletions of putative functional domains, generate highly unstable products. Cells from AOA1 patients are characterized by enhanced sensitivity to agents that cause single-strand breaks in DNA but there is no evidence for a gross defect in single-strand break repair. Sensitivity to hydrogen peroxide and the resulting genome instability are corrected by transfection with full-length aprataxin cDNA. We also demonstrate that aprataxin interacts with the repair proteins XRCC1, PARP-1 and p53 and that it co-localizes with XRCC1 along charged particle tracks on chromatin. These results demonstrate that aprataxin influences the cellular response to genotoxic stress very likely by its capacity to interact with a number of proteins involved in DNA repair.

DOI： 10.1093/hmg/ddh122

　前のページ - 次のページ　

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25