Friedreich's ataxia: the vicious circle hypothesis revisited

被引:55
作者
Bayot, Aurelien [1 ,2 ]
Santos, Renata [3 ]
Camadro, Jean-Michel [3 ]
Rustin, Pierre [1 ,2 ]
机构
[1] CHU Hop Robert Debre, INSERM, Physiopathol & Therapy Mitochondrial Dis Lab, U676, F-75019 Paris, France
[2] Univ Paris Diderot, Fac Med Denis Diderot, IFR02, F-75018 Paris, France
[3] Univ Paris Diderot, Inst Jacques Monod, Mitochondria Met & Oxidat Stress Lab, UMR CNRS 7592, F-75205 Paris 13, France
关键词
LINKED SIDEROBLASTIC ANEMIA; OXIDATIVE STRESS; VITAMIN-E; YEAST FRATAXIN; MOUSE MODELS; IRON; DEFICIENCY; MUTATION; GENE; ANTIOXIDANT;
D O I
10.1186/1741-7015-9-112
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Friedreich's ataxia, the most frequent progressive autosomal recessive disorder involving the central and peripheral nervous systems, is mostly associated with unstable expansion of GAA trinucleotide repeats in the first intron of the FXN gene, which encodes the mitochondrial frataxin protein. Since FXN was shown to be involved in Friedreich's ataxia in the late 1990s, the consequence of frataxin loss of function has generated vigorous debate. Very early on we suggested a unifying hypothesis according to which frataxin deficiency leads to a vicious circle of faulty iron handling, impaired iron-sulphur cluster synthesis and increased oxygen radical production. However, data from cell and animal models now indicate that iron accumulation is an inconsistent and late event and that frataxin deficiency does not always impair the activity of iron-sulphur cluster-containing proteins. In contrast, frataxin deficiency appears to be consistently associated with increased sensitivity to reactive oxygen species as opposed to increased oxygen radical production. By compiling the findings of fundamental research and clinical observations we defend here the opinion that the very first consequence of frataxin depletion is indeed an abnormal oxidative status which initiates the pathogenic mechanism underlying Friedreich's ataxia.
引用
收藏
页数:8
相关论文
共 70 条
[1]   Bacterial frataxin CyaY is the gatekeeper of iron-sulfur cluster formation catalyzed by IscS [J].
Adinolfi, Salvatore ;
Iannuzzi, Clara ;
Prischi, Filippo ;
Pastore, Chiara ;
Iametti, Stefania ;
Martin, Stephen R. ;
Bonomi, Franco ;
Pastore, Annalisa .
NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2009, 16 (04) :390-396
[2]   GAA repeat expansion mutation mouse models of Friedreich ataxia exhibit oxidative stress leading to progressive neuronal and cardiac pathology [J].
Al-Mahdawi, Sahar ;
Pinto, Ricardo Mouro ;
Varshney, Dhaval ;
Lawrence, Lorraine ;
Lowrie, Margaret B. ;
Hughes, Sian ;
Webster, Zoe ;
Blake, Julian ;
Cooper, J. Mark ;
King, Rosalind ;
Pook, Mark A. .
GENOMICS, 2006, 88 (05) :580-590
[3]   Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A) [J].
Allikmets, R ;
Raskind, WH ;
Hutchinson, A ;
Schueck, ND ;
Dean, M ;
Koeller, DM .
HUMAN MOLECULAR GENETICS, 1999, 8 (05) :743-749
[4]   Does oxidative stress contribute to the pathology of Friedreich's ataxia? A radical question [J].
Armstrong, Jeffrey S. ;
Khdour, Omar ;
Hecht, Sidney M. .
FASEB JOURNAL, 2010, 24 (07) :2152-2163
[5]   Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin [J].
Babcock, M ;
deSilva, D ;
Oaks, R ;
DavisKaplan, S ;
Jiralerspong, S ;
Montermini, L ;
Pandolfo, M ;
Kaplan, J .
SCIENCE, 1997, 276 (5319) :1709-1712
[6]  
Bekri S, 2000, BLOOD, V96, P3256
[7]   Genetic background influences mitochondrial function: modeling mitochondrial disease for therapeutic development [J].
Benit, Paule ;
El-Khoury, Riyad ;
Schiff, Manuel ;
Sainsard-Chanet, Annie ;
Rustin, Pierre .
TRENDS IN MOLECULAR MEDICINE, 2010, 16 (05) :210-217
[8]   The Variability of the Harlequin Mouse Phenotype Resembles that of Human Mitochondrial-Complex I-Deficiency Syndromes [J].
Benit, Paule ;
Goncalves, Sergio ;
Dassa, Emmanuel Philippe ;
Briere, Jean-Jacques ;
Rustin, Pierre .
PLOS ONE, 2008, 3 (09)
[9]   Oxidative stress and protease dysfunction in the yeast model of Friedreich ataxia [J].
Bulteau, Anne-Laure ;
Dancis, Andrew ;
Gareil, Monique ;
Montagne, Jean-Jacques ;
Camadro, Jean-Michel ;
Lesuisse, Emmanuel .
FREE RADICAL BIOLOGY AND MEDICINE, 2007, 42 (10) :1561-1570
[10]   Mitochondrial ATP-binding cassette proteins [J].
Burke, Michael A. ;
Ardehali, Hossein .
TRANSLATIONAL RESEARCH, 2007, 150 (02) :73-80