Triosephosphate isomerase deficiency: consequences of an inherited mutation at mRNA, protein and metabolic levels.

Triosephosphate isomerase (TPI) deficiency is a unique glycolytic enzymopathy coupled with neurodegeneration. Two Hungarian compound heterozygote brothers inherited the same TPI mutations (F240L and E145Stop), but only the younger one suffers from neurodegeneration. In the present study, we determined the kinetic parameters of key glycolytic enzymes including the mutant TPI for rational modelling of erythrocyte glycolysis.

Functional aspects of cellular microcompartmentation in the development of neurodegeneration: mutation induced aberrant protein-protein associations.

Research in the last 10 years has revealed that the development of neurodegeneration is a multistep process during which one or few specific mutant protein species of altered conformation initiate aberrant protein-protein interactions resulting in aggregates forming plaques. This review focuses on the heteroassociations of the mutant proteins with subcellular structures, such as cytoskeleton, cell membranes or with glycolytic enzymes, which may be crucial in the initiation of neurodegeneration such as in Huntington's disease or Alzheimer's disease. Triosephosphate isomerase enzymopathy is a unique glycolytic enzyme deficiency coupled with neurodegeneration.

Adverse effects of dopamine potentiation by long-term treatment with selegiline.

A patient with triosephosphate isomerase (TPI) deficiency exhibited worsening of abnormal involuntary movements of the dystonic type and developed psychiatric symptoms while on selegiline. When selegiline was stopped after 9 years of treatment, abnormal involuntary movements improved to pretreatment level and psychiatric behaviour returned to normal. Monoamine oxidase-B platelet activity was low in this patient.

Increased formation of methylglyoxal and protein glycation, oxidation and nitrosation in triosephosphate isomerase deficiency.

Triosephosphate isomerase deficiency is associated with the accumulation of dihydroxyacetonephosphate (DHAP) to abnormally high levels, congenital haemolytic anaemia and a clinical syndrome of progressive neuromuscular degeneration leading to infant mortality. DHAP degrades spontaneously to methylglyoxal (MG)--a potent precursor of advanced glycation endproducts (AGEs). MG is detoxified to D-lactate intracellularly by the glyoxalase system.

Triosephosphate isomerase deficiency: a neurodegenerative misfolding disease.

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.