title: Triosephosphate isomerase deficiency: a neurodegenerative misfolding disease.
abstract: 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 (Phe(240)-->Leu and Glu(145)-->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 fluores cence 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.
authors.affiliation: Institute of Enzymology, Hungarian Academy of Sciences, P.O. Box 7, Budapest H-1518, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Oláh
authors.forename: Ferenc
authors.initials: F
authors.lastname: Orosz
authors.forename: György M
authors.initials: GM
authors.lastname: Keserü
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Kovári
authors.forename: János
authors.initials: J
authors.lastname: Kovács
authors.forename: Susan
authors.initials: S
authors.lastname: Hollán
authors.forename: Judit
authors.initials: J
authors.lastname: Ovádi
mesh_terms: D004795:Enzyme Stability; D006019:Glycolysis; D020271:Heredodegenerative Disorders, Nervous System / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008297:Male; D008870:Microtubules / Q000201:enzymology / Q000648:ultrastructure; D008958:Models, Molecular; D009154:Mutation; D010427:Pentose Phosphate Pathway; D017510:Protein Folding; D014305:Triose-Phosphate Isomerase / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D014305:Triose-Phosphate Isomerase