|
|
|
Internaf-News June 1999 Page 3 Back to Index
J Physiol (Lond) 1999 Jul 1;518(Pt 1):1-12 Rolfs A, Hediger MA Membrane Biology Program and Renal Division, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, and Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.[Record supplied by publisher] Despite the importance of metal ions in several catalytic functions, there has been, until recently, little molecular information available on the mechanisms whereby metal ions are actively taken up by mammalian cells. The classical concept for iron uptake into mammalian cells has been the endocytosis of transferrin-bound Fe3+ by the transferrin receptor. Studies with hypotransferrinaemic mice revealed that in the intestine mucosal transferrin is derived from the plasma and that its presence is not required in the intestinal lumen for dietary iron absorption. This suggests that, at least in the intestine, other non-receptor-mediated uptake systems exist. The molecular identification of metal ion transporters is of great importance, in particular since an increasing number of human diseases are thought to be related to disturbances in metal ion homeostasis, including metal ion overload and deficiency disorders (i.e. anaemia, haemochromatosis, Menkes disease, Wilson's disease), and neurodegenerative diseases (i.e. Alzheimer's, Friedreich's ataxia and Parkinson's diseases). Furthermore, susceptibilities to mycobacterial infections are caused by metal ion transporter defects. The pathological implications of disturbed metal ion homeostasis confirm the vital roles these metal ions play in the catalytic function of many enzymes, in gene regulation (zinc-finger proteins), and in free radical homeostasis. Recent insights have significantly advanced our knowledge of how metal ions are taken up or released by mammalian cells. The purpose of this review is to summarize these advances and to give an overview on the growing number of mammalian metal ion transporters. PMID: 10373684
June 28 — Using cell engineering techniques, scientists may have found a way to generate unlimited supplies of brain cells for transplanting into Parkinson’s disease patients. The work focuses on neural stem cells — the building blocks for all our brain and nervous system cells. RESTORING brain function by cell replacement is considered a new therapeutic strategy with great potential for treating human disorders of the brain and nervous system. And trials have demonstrated that the basic principle works for patients with Parkinson’s disease. But the source of those cells has been problematic, points out Dr.Olle Lindvall of the University Hospital in Lund, Sweden, who wrote an editorial accompanying the new study. Getting them from aborted fetuses is controversial, and taking cells from animals raises concern about introducing new diseases into people. And while stem cells can be grown in batches in the lab, researchers were unsure how to coax them to specifically develop into the type of nerve cells that are needed to correct the underlying defect in people with Parkinson’s — cells that produce the chemical dopamine. But now, in mice studies, an international team of researchers has elucidated those signals for the first time. If applicable to human cells, their approach could provide a potentially unlimited source of neurons for use in cell replacement therapies for Parkinson’s patients. For the new study, reported in the July issue of the journal Nature Biotechnology, researchers from the Karolinska Institute in Stockholm, Harvard Medical School and elsewhere used stem cells from mice. They gave the stem cells genes that encourage development of dopamine-making cells, and exposed them to other cells called astrocytes that provided chemical signals for proper development. Mouse brains injected with the neurons retained live transplanted cells for two weeks, the study showed, even in the absence of growth factors and supportive cells. The results are important but there are some caveats, Lindvall said. Human transplantation might require stem cells from people rather than mice. And it’s not clear whether brain cells produced this way would really ease Parkinson’s symptoms. But he and others are excited about the possibilities. LOTS OF WIGGLE ROOM "There is lots of wiggle room in the nervous system, especially at the level of stem cells," says Evan Snyder, an assistant professor of neurology at Harvard. "So we can tap into the natural plasticity of the seeds and exploit them." Snyder compares the diseased brain to a trampled lawn — "perhaps a lawn that didn’t grow right or was destroyed by the kids biking or by the weather." Just as you would grow new grass by seeding the lawn, you can sprout healthy tissue by seeding the "broken" brain — with neural stem cells. Snyder’s own work shows that in mice genetically engineered to suffer from human strokes, neural stem cells have an affinity for the area of brain injury. Once there, the cells integrate seamlessly into the surrounding brain tissue, maturing into the type of tissue appropriate for the particular area of the brain. But he agrees that questions still remain. While, in all the experiments, the grafted cells integrated seamlessly into the surrounding brain tissue, it remains to be seen if they actually function. He plans to start human trials within two years to find out. The Associated Press contributed to this report.
Abstracts - January 1999 Spinocerebellar Ataxia Type 2Clinical Features of a Pedigree Displaying Prominent Frontal-Executive DysfunctionElsdon Storey, PhD; Susan M. Forrest, PhD; Janet H. Shaw, BS; Peter Mitchell, FRACR; R. J. McKinley Gardner, FRACP Background: Spinocerebellar ataxia type 2 (SCA2) is a recently delineated cause of autosomal dominant cerebellar ataxia type I. The basic clinical neurologic features of SCA2 have been described in the literature, but neuropsychological features have not, despite statements that some patients became demented. For further info go to : http://www.ama-assn.org/sci-pubs/journals/archive/neur/vol_56/no_1/noc7702a.htm
Arq Neuropsiquiatr 1999 Mar;57(1):1-5 Clinical and molecular studies in five Brazilian cases of Friedreich ataxia.Schwartz IV, Jardim LB, Puga AC, Cocozza S, Leistner S, Lima LCServico de Genetica Medica, Hospital de Clinicas de Porto Alegre, Brasil. ida@ez-poa.com.br [Medline record in process] Friedreich's ataxia (FRDA), the most common autosomal recessive ataxia, is caused in 94% of cases by homozygous expansions of an unstable GAA repeat localised in intron 1 of the X25 gene. We have investigated this mutation in five Brazilian patients: four with typical FRDA findings and one patient with atypical manifestations, who was considered to have some other form of cerebellar ataxia with retained reflexes. The GAA expansion was detected in all these patients. The confirmation of FRDA diagnosis in the atypical case may be pointing out, as in other reports, that clinical spectrum of Friedreich's ataxia is broader than previously recognised and includes cases with intact tendon reflexes.
Hum Mol Genet 1999 Jun;8(6):1099-1110 Mitochondrial intermediate peptidase and the yeast frataxin homolog together maintain mitochondrial iron homeostasis in Saccharomyces cerevisiae.Branda SS, Yang Z, Chew A, Isaya GDepartment of Pediatric and Adolescent Medicine, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA [Record supplied by publisher] Friedreich's ataxia (FRDA) is a neuro degrees enerative disease typically caused by a deficiency of frataxin, a mitochondrial protein of unknown function. In Saccharomyces cerevisiae, lack of the yeast frataxin homolog ( YFH1 gene, Yfh1p polypeptide) results in mitochondrial iron accumulation, suggesting that frataxin is required for mitochondrial iron homeostasis and that FRDA results from oxidative damage secondary to mitochondrial iron overload. This hypothesis implies that the effects of frataxin deficiency could be influenced by other proteins involved in mitochondrial iron usage. We show that Yfh1p interacts functionally with yeast mitochondrial intermediate peptidase ( OCT1 gene, YMIP polypeptide), a metalloprotease required for maturation of ferrochelatase and other iron-utilizing proteins. YMIP is activated by ferrous iron in vitro and loss of YMIP activity leads to mitochondrial iron depletion, suggesting that YMIP is part of a feedback loop in which iron stimulates maturation of YMIP substrates and this in turn promotes mitochondrial iron uptake. Accordingly, YMIP is active and promotes mitochondrial iron accumulation in a mutant lacking Yfh1p ( yfh1 [Delta]), while genetic inactivation of YMIP in this mutant ( yfh1 [Delta] oct1 [Delta]) leads to a 2-fold reduction in mitochondrial iron levels. Moreover, overexpression of Yfh1p restores mitochondrial iron homeostasis and YMIP activity in a conditional oct1 ts mutant, but does not affect iron levels in a mutant completely lacking YMIP ( oct1 [Delta]). Thus, we propose that Yfh1p maintains mitochondrial iron homeostasis both directly, by promoting iron export, and indirectly, by regulating iron levels and therefore YMIP activity, which promotes mitochondrial iron uptake. This suggests that human MIP may contribute to the functional effects of frataxin deficiency and the clinical manifestations of FRDA. PMID: 10332043
The Friedreich's ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis. Wong A, Yang J, Cavadini P, Gellera C, Lonnerdal B, Taroni F, Cortopassi GDepartment of Molecular Biosciences, 1311 Haring Hall, University of California, Davis, CA 95616, USA. Expansions of an intronic GAA repeat reduce the expression of frataxin and cause Friedreich's ataxia (FRDA), an autosomal recessive neurodegenerative disease. Frataxin is a mitochondrial protein, and disruption of a frataxin homolog in yeast results in increased sensitivity to oxidant stress, increased mitochondrial iron and respiration deficiency. These previous data support the hypothesis that FRDA is a disease of mitochondrial oxidative stress, a hypothesis we have tested in cultured cells from FRDA patients. FRDA fibroblasts were hypersensitive to iron stress and significantly more sensitive to hydrogen peroxide than controls. The iron chelator deferoxamine rescued FRDA fibroblasts more than controls from oxidant-induced death, consistent with a role for iron in the differential kinetics of death; however, mean mitochondrial iron content in FRDA fibroblasts was increased by only 40%. Treatment of cells with the intracellular Ca2+chelator BAPTA-AM rescued both FRDA fibroblasts and controls from oxidant-induced death. Treatment with apoptosis inhibitors rescued FRDA but not control fibroblasts from oxidant stress, and staurosporine-induced caspase 3 activity was higher in FRDA fibroblasts, consistent with the possibility that an apoptotic step upstream of caspase 3 is activated in FRDA fibroblasts. These results demonstrate that FRDA fibroblasts are sensitive to oxidant stress, and may be a useful model in which to elucidate the FRDA mechanism and therapeutic strategies. PMID: 9949201, UI: 99138689
Direct evidence that mitochondrial iron accumulation occurs in Friedreich ataxia.Delatycki MB, Camakaris J, Brooks H, Evans-Whipp T, Thorburn DR, Williamson R, Forrest SMThe Murdoch Institute, Royal Children's Hospital, Parkville, Victoria, Australia. Friedreich ataxia (FRDA) is due to mutations in the FRDA gene (FRDA). When the gene homologous to FRDA is knocked out in yeast, there is accumulation of iron in mitochondria and reduced respiratory function. So far, there is only indirect evidence to support the hypothesis that FRDA is due to accumulation of mitochondrial iron leading to increased production of free radicals. We show here that mitochondrial iron is significantly higher in fibroblasts from patients with FRDA than in control fibroblasts. This is the first direct evidence that the findings in yeast are reproducible in cells from patients with FRDA. PMID: 10319894, UI: 99251612
The mouse SCA2 gene: cDNA sequence, alternative splicing and protein expression. Nechiporuk T, Huynh DP, Figueroa K, Sahba S, Nechiporuk A, Pulst SMRose Moss Laboratory for Parkinson's and Neurodegenerative Diseases, CSMC Burns and Allen Research Institute and Division of Neurology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA. Spinocerebellar ataxia type 2 (SCA2) is caused by expansion of a CAG trinucleotide repeat located in the coding region of the human SCA2 gene. Sequence analysis revealed that SCA2 is a novel gene of unknown function. In order to provide insights into the molecular mechanisms of pathogenesis of SCA2 and to identify conserved domains, we isolated and characterized the mouse homolog of the SCA2 gene. Sequence and amino acid analysis revealed 89% identity at the nucleotide and 91% identity at the amino acid level. However, there was no extended polyglutamine tract in the mouse SCA2 cDNA, suggesting that the normal function of SCA2 is not dependent on this domain. Northern blot analysis of different mouse tissues indicated that the mouse SCA2 gene was expressed in most tissues, but at varying levels. Alternative splicing seen in human SCA2 was conserved in the mouse. By northern blot analysis, SCA2 was expressed during embryogenesis as early as day 8 of gestation (E8). Immunohistochemical staining using affinity-purified antibodies demonstrated that ataxin 2 was expressed in the cytoplasm of Purkinje cells as well as in other neurons of the CNS. PMID: 9668173, UI: 98334550
|
|
Contact Information Electronic mail For General Information: owner-internaf@connect.org.uk Send mail to chris.mo@cwcom.net
with questions or comments about this web site. |
