A number of neurodegenerative diseases are mediated by mutation-induced protein misfolding. The resulting genetic defects, however, are expressed in varying phenotypes. Of the several well-established glycolytic enzyme deficiencies, triosephosphate isomerase (TPI) deficiency is the only one in which haemolytic anaemia is coupled with progressive, severe neurological disorder. In a Hungarian family with severe decrease in TPI activity, two germ line-identical but phenotypically differing compound heterozygote brothers inherited two independent (Phe240 → Leu and Glu145 → stop codon) mutations. We have demonstrated recently [Orosz, Oláh, Alvarez, Keserü, Szabó, Wágner, Kovári, Horányi, Baróti, Martial, Hollán and Ovádi (2001) Blood 98, 3106–3112] that the mutations of TPI explain in themselves neither the severe decrease in the enzyme activity characteristic of TPI deficiency nor the enhanced ability of the mutant enzyme from haemolysate of the propositus to associate with subcellular particles. Here we present kinetic (flux analysis), thermodynamic (microcalorimetry and fluorescence spectroscopy), structural (in silico) and ultrastructural (immunoelectron microscopy) data for characterization of mutant isomerase structures and for the TPI-related metabolic processes in normal and deficient cells. The relationships between mutation-induced TPI misfolding and formation of aberrant protein aggregates are discussed.
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Conference Article|
April 01 2002
Triosephosphate isomerase deficiency: a neurodegenerative misfolding disease
Judit Oláh;
Judit Oláh
*Institute of Enzymology, Hungarian Academy of Sciences, Budapest, H-1518, P.O. Box 7, Hungary
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Ferenc Orosz;
Ferenc Orosz
*Institute of Enzymology, Hungarian Academy of Sciences, Budapest, H-1518, P.O. Box 7, Hungary
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György M. Keserü;
György M. Keserü
†Chemical Works of Gedeon Richter Ltd., Budapest, Hungary
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Zoltán Kovári;
Zoltán Kovári
†Chemical Works of Gedeon Richter Ltd., Budapest, Hungary
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János Kovács;
János Kovács
‡Department of General Zoology, University of Eötvös Loránd, Budapest, Hungary
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Susan Hollán;
Susan Hollán
§National Institute of Blood Transfusion, Budapest, Hungary
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Judit Ovádi
Judit Ovádi
1
*Institute of Enzymology, Hungarian Academy of Sciences, Budapest, H-1518, P.O. Box 7, Hungary
1To whom correspondence should be addressed (e-mail ovadi@enzim.hu).
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Publisher: Portland Press Ltd
Received:
November 19 2001
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2002 Biochemical Society
2002
Biochem Soc Trans (2002) 30 (2): 30–38.
Article history
Received:
November 19 2001
Citation
Judit Oláh, Ferenc Orosz, György M. Keserü, Zoltán Kovári, János Kovács, Susan Hollán, Judit Ovádi; Triosephosphate isomerase deficiency: a neurodegenerative misfolding disease. Biochem Soc Trans 1 April 2002; 30 (2): 30–38. doi: https://doi.org/10.1042/bst0300030
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