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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic programs and age-dependent changes in DNA and protein are involved in aging. The genetic program governs body weight, longevity, aging rate, sex-maturating period and metabolic rate in mammals, and such a number of life history variables are highly correlated with body size. Monogenic age-1 and daf-2 C. elegans mutants extend life span twice. However, human monogenic progeroids shorten lifespan. The Werner syndrome gene was mapped in 8p12. Mutations in the Cockayne syndrome genes (the CSA and CSB genes acting for preferential repair of active genes by interacting with transcription factor TFIIH) and in the ataxia telangictasia gene ATM (homologous with PI-3 kinase for signal transduction) have been disclosed. All such findings suggest a strong basis for the genetic program of aging. In addition, recent evidence indicates that genetic instability, such as telomere loss, somatic and mitochondrial DNA mutations, increases with age. In addition, amounts of carbonylated protein also increase during human aging, and greatly increase in an SOD-deficient C. elegans mutant, but to a less extent in long-living age-1. Therefore, the aging process involves gene action, genetic instability and protein oxidation. Dietary restriction and elimination of deleterious excessive reactive oxygen species may improve many abnormalities due to aging.
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PMID:[The mechanisms of aging and perspective for elimination of deleterious effects]. 889 Jun 1

There exist numerous genetic disorders, marked by chromosome instability, that are strikingly associated with various cancers. Both the chromosomal instabilities and neoplastic outcomes are related to abnormalities of DNA metabolism, DNA repair, cell-cycle governance, or control of apoptosis. Among these diseases are ataxia telangectasia and Nijmegen breakage syndrome, with increased incidences of lymphomas. Bloom syndrome, Werner syndrome, and Rothmund-Thompson syndrome, each characterized by a DNA helicase defect, are associated with early incidences of different cancers. Other diseases combining the phenotype of chromosomal instabilities and neoplastic development are Fanconi anemia and breast cancers associated with mutant BRCA1 and BRCA2 genes. The cloning of the encoding genes and the characterization of their products have resulted in partial understanding of the pathways of cellular DNA surveillance and maintenance of genomic rectitude. The exact pathways fully linking the genetic defect mechanisms to the eventual development of various neoplasias remain to be elucidated, but progress in defining the molecular genetics of these entities suggests that many of them are disorders of DNA recombination. Each defect involves a separate protein in these complex pathways.
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PMID:Chromosome breakage syndromes and cancer. 1240 92

We review the genes and proteins related to the homologous recombinational repair (HRR) pathway that are implicated in cancer through either genetic disorders that predispose to cancer through chromosome instability or the occurrence of somatic mutations that contribute to carcinogenesis. Ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS), and an ataxia-like disorder (ATLD), are chromosome instability disorders that are defective in the ataxia telangiectasia mutated (ATM), NBS, and Mre11 genes, respectively. These genes are critical in maintaining cellular resistance to ionizing radiation (IR), which kills largely by the production of double-strand breaks (DSBs). Bloom syndrome involves a defect in the BLM helicase, which seems to play a role in restarting DNA replication forks that are blocked at lesions, thereby promoting chromosome stability. The Werner syndrome gene (WRN) helicase, another member of the RecQ family like BLM, has very recently been found to help mediate homologous recombination. Fanconi anemia (FA) is a genetically complex chromosomal instability disorder involving seven or more genes, one of which is BRCA2. FA may be at least partially caused by the aberrant production of reactive oxidative species. The breast cancer-associated BRCA1 and BRCA2 proteins are strongly implicated in HRR; BRCA2 associates with Rad51 and appears to regulate its activity. We discuss in detail the phenotypes of the various mutant cell lines and the signaling pathways mediated by the ATM kinase. ATM's phosphorylation targets can be grouped into oxidative stress-mediated transcriptional changes, cell cycle checkpoints, and recombinational repair. We present the DNA damage response pathways by using the DSB as the prototype lesion, whose incorrect repair can initiate and augment karyotypic abnormalities.
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PMID:Recombinational DNA repair and human disease. 1242 31

A comparative evaluation is reported of pro-oxidant states in 82 patients with ataxia telangectasia (AT), Bloom syndrome (BS), Down syndrome (DS), Fanconi anemia (FA), Werner syndrome (WS), and xeroderma pigmentosum (XP) vs 98 control donors. These disorders display cancer proneness, and/or early aging, and/or other clinical features. The measured analytes were: (a) leukocyte and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), (b) blood glutathione (GSSG and GSH), (c) plasma glyoxal (Glx) and methylglyoxal (MGlx), and (d) some plasma antioxidants [uric acid (UA) and ascorbic acid (AA)]. Leukocyte 8-OHdG levels ranked as follows: WS>BS approximately FA approximately XP>DS approximately AT approximately controls. Urinary 8-OHdG levels were significantly increased in a total of 22 patients with BS, FA, or XP vs 47 controls. The GSSG:GSH ratio was significantly increased in patients with WS and in young (< or =15 years) patients with DS or with FA and decreased in older patients with DS or FA and in AT, BS, and XP patients. The plasma levels of Glx and/or MGlx were significantly increased in patients with WS, FA, and DS. The UA and AA levels were significantly increased in WS and DS patients, but not in AT, FA, BS, nor XP patients. Rationale for chemoprevention trials is discussed.
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PMID:Different patterns of in vivo pro-oxidant states in a set of cancer- or aging-related genetic diseases. 1805 16

The process of skin aging in humans is complex and is induced by multiple factors, including genetic and various environmental ones. In particular, the superposition of environmental factors, such as UV irradiation on skin, results in massive wound-like morphological alterations mainly of the dermis. In sun-protected areas the most pronounced changes occur within the epidermis and affect mostly the basal cell layer. As a result, while sun-protected aged skin appears thin, finely wrinkled, and dry, photoaged skin is characterized by deep wrinkles, laxity, and roughness. Although the fundamental mechanisms are still poorly understood, a growing body of evidence points toward the involvement of multiple pathways in the generation of aged skin. Recent data obtained by expression-profiling studies and studies of progeroid syndromes (e.g., Hutchinson-Gilford progeria, Werner syndrome, Rothmund-Thomson syndrome, Cockayne syndrome, ataxia teleangiectasia, and Down syndrome) illustrate that among the most important biological processes involved in skin aging are alterations in DNA repair and stability, mitochondrial function, cell cycle and apoptosis, ubiquitin-induced proteolysis, and cellular metabolism. One of the major factors that has been proposed to play an exquisite role in the initiation of aging is the physiological hormone decline occurring with age. However, hormones at age-specific levels may not only regulate age-associated mechanisms but also regulate tumor-suppressor pathways that influence carcinogenesis. Understanding the molecular mechanisms of aging may open new strategies in dealing with the various diseases accompanying aging, including cancer.
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PMID:Molecular mechanisms of skin aging: state of the art. 1805 53

Werner syndrome (WS) is a human genetic disorder characterized by extensive clinical features of premature aging. Ataxia-telengiectasia (A-T) is a multisystem human genomic instability syndrome that includes premature aging in some of the patients. WRN and ATM, the proteins defective in WS and A-T, respectively, play significant roles in the maintenance of genomic stability and are involved in several DNA metabolic pathways. A role for WRN in DNA repair has been proposed; however, this study provides evidence that WRN is also involved in ATM pathway activation and in a S-phase checkpoint in cells exposed to DNA interstrand cross-link-induced double-strand breaks. Depletion of WRN in such cells by RNA interference results in an intra-S checkpoint defect, and interferes with activation of ATM as well as downstream phosphorylation of ATM target proteins. Treatment of cells under replication stress with the ATM kinase inhibitor KU 55933 results in a S-phase checkpoint defect similar to that observed in WRN shRNA cells. Moreover, gamma H2AX levels are higher in WRN shRNA cells than in control cells 6 and 16 h after exposure to psoralen DNA cross-links. These results suggest that WRN and ATM participate in a replication checkpoint response, in which WRN facilitates ATM activation in cells with psoralen DNA cross-link-induced collapsed replication forks.
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PMID:WRN is required for ATM activation and the S-phase checkpoint in response to interstrand cross-link-induced DNA double-strand breaks. 1859 39

The presence of aggregates of abnormally expanded polyglutamine (polyQ)-containing proteins are a pathological hallmark of a number of neurodegenerative diseases including Huntington's disease (HD) and spinocerebellar ataxia-3 (SCA3). Previous studies in cellular, Drosophila, and mouse models of HD and SCA have shown that neurodegeneration can be prevented by manipulations that inhibit polyQ aggregation. We have shown that the UL97 kinase of the human cytomegalovirus (HCMV) prevents aggregation of the pp71 and pp65 viral tegument proteins. To explore whether UL97 may act as a general antiaggregation factor, we examined whether UL97 prevents aggregation of cellular non-polyQ and polyQ proteins. We report that UL97 prevents the deposition of aggregates of two non-polyQ proteins: a protein chimera (GFP170*) composed of the green fluorescent protein and a fragment of the Golgi Complex protein (GCP-170) and a chimera composed of the red fluorescent protein (RFP) fused to the Werner syndrome protein (WRN), a RecQ helicase and exonuclease involved in DNA repair. Furthermore, we show that UL97 inhibits aggregate deposition in cellular models of HD and SCA3. UL97 prevents the deposition of aggregates of the mutant huntingtin exon 1 containing 82 glutamine repeats (HttExon1-Q82) or full length ataxin-3 containing a 72 polyQ track (AT3-72Q). The kinase activity of UL97 appears critical, as the kinase-dead UL97 mutant (K335M) fails to prevent aggregate formation. We further show that UL97 disrupts nuclear PML bodies and decreases p53-mediated transcription. The universality of the antiaggregation effect of UL97 suggests that UL97 targets a key cellular factor that regulates cellular aggregation mechanisms. Our results identify UL97 as a novel means to modulate polyQ aggregation and suggest that UL97 can serve as a novel tool to probe the cellular mechanisms that contribute to the formation of aggregates in polyglutamine disorders.
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PMID:Human cytomegalovirus UL97 kinase prevents the deposition of mutant protein aggregates in cellular models of Huntington's disease and ataxia. 2073 21

Well-differentiated thyroid cancer accounts for 95% of thyroid malignancies. In contrast to medullary thyroid carcinoma, in which about 25% are familial, only 5% of follicular cell-derived thyroid carcinomas are a component of a familial cancer syndrome. The familial follicular cell-derived tumors or nonmedullary thyroid carcinoma encompass a heterogeneous group of diseases, and are classified into 2 distinct groups: syndromic-associated tumors, occurring in syndromes in which nonmedullary thyroid carcinomas are the predominant tumor encountered, and nonsyndromic tumors, those occurring in tumor syndromes in which thyroid involvement is a minor component. The first group, syndromic-associated tumors, includes phosphase and tensin (PTEN)-hamartoma tumor syndrome/Cowden syndrome, familial adenomatous polyposis/Gardner syndrome, Carney complex type 1, Werner syndrome, and Pendred syndrome. Other syndromes, as McCune Albright syndrome, Peutz-Jeghers syndrome, and Ataxia-teleangiectasia syndrome may be associated with the development of follicular cell-derived tumors, but the link is less established than the above syndromes. The syndromic-associated tumors are the focus of this review. The second group of familial follicular cell-derived tumors syndromes or nonsyndromic tumors, in which nonmedullary thyroid carcinomas are the major findings, include pure familial papillary thyroid carcinoma, with or without oxyphilia, familial papillary thyroid carcinoma with papillary renal cell carcinoma, and familial papillary thyroid carcinoma with multinodular goiter. This review will discuss the clinical and pathological findings of the patients with familial syndrome-associated tumors: PTEN-hamartoma tumor syndrome/Cowden syndrome, familial adenomatous polyposis syndrome, Carney complex type 1, Werner syndrome, and Pendred syndrome.
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PMID:Thyroid cancer of follicular cell origin in inherited tumor syndromes. 2096 48

Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby causing Huntington's disease. Single-strand breaks are common DNA lesions and are associated with the neurodegenerative diseases, ataxia-oculomotor apraxia-1 and spinocerebellar ataxia with axonal neuropathy-1. DNA double-strand breaks are toxic lesions and two main pathways exist for their repair: homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage may be linked with the age-associated neurodegenerative disorders Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Mutation in the WRN protein leads to the premature aging disease Werner syndrome, a disorder that features neurodegeneration. In this article we review the evidence linking deficiencies in the DNA repair pathways with neurodegeneration.
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PMID:DNA repair deficiency in neurodegeneration. 2155 Mar 79

DNA repair is involved in maintaining the stability of the genome and accurate sending of genetic information. DNA repair pathways remove many DNA damages induced by endo- and exogenous factors. There are several DNA repair pathways in human cells, including base or nucleotide excision system, homologous recombination system and non-homologous end joining. Mutation in DNA repair genes may results in rare genetic disorders, including Xeroderma pigmentosum, Cockayne syndrom, trichothiodystrophy, Nijmegen syndrome, ataxia teleangiectasia, Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome. These diseases may be associated with various visual disturbances. In this work we review we focus on human genetic diseases linked with mutations in DNA repair genes associated with visual impairment.
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PMID:[Ocular manifestations in hereditary diseases with defects in DNA repair]. 2534 96


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