title: [Glycolytic enzyme defects and neurodegeneration].
abstract: This study was devoted to the continued search for an explanation of the neurodegeneration found in a severely TPI deficient Hungarian patient whose brother with genomically completely identical TPI defect was completely free of neurological disorders. The changes found in the molecular species composition of the major PL subclasses and the decrease in PE plasmalogens explain the earlier round increase in membrane fluidity interfering thereby with the physiological function of membrane enzymes, receptors, signal transduction, protein-protein interactions and vesicle fusion. Plasmalogens have also the capacity to protect against oxidative stress, that is deemed to contribute to neurodegenerative processes. The presence of chronic oxidative stress was well reflected in the decreased levels of GSH and alpha-tocopherol in the affected brothers. Decrease in plasmalogens have been described recently in Zellweger's syndrome, in other peroxisomal neurodegenerative disorders, in demyelinating processes and in Alzheimer's disease. The brain in normal individuals is highly enriched in plasmalogens. The pathological decrease found in TPI deficient lymphocytes will presumably be more pronounced in excitatory tissues. The recently described role of expanding nucleotide triplets in the development of neurodegeneration is suggested to result through the selective binding via their polyglutamine repeats to GAPDH. The role of GAPDH in TPI deficiency may be of crucial help in the elucidation of the development of neurodegeneration, since the enzymatic defect of TPI can be partially bypassed by means of the HMP shunt which generates GAP via GAPDH without the participation of TPI. Considering the results found in TPI deficiency in comparison to the new literary findings in different neurodegenerative diseases the following pathomechanism may be proposed. The protein products of the defective genes due to their abnormal steric structure bind GAPDH in a different manner or in differing quantity than their normal counterparts. The PL composition and the resulting differences in the biophysical properties of the cell membranes have crucial impact on these protein-protein interactions and on the activity of enzymes and membrane transport functions. The plasmalogen decrease impairs the protection against oxidative stress with consecutive worsening of the neurodegenerative process. The final common pathway to neuronal death leads through destabilization of intracellular Ca2+ homeostasis via elevation of intracellular Ca2+ to apoptosis. The most important conclusion is that lipids are not an inert environment of membrane proteins. Unravelling of the pathogenesis of neurodegeneration needs more concerted investigation of the interactions between genetic changes with biophysical and biochemical cell membrane lipid alterations.
authors.affiliation: Institut National de Transfusion Sanguine, Budapest, Hongrie.
authors.forename: S
authors.initials: S
authors.lastname: Hollán
authors.forename: L
authors.initials: L
authors.lastname: Vécsei
authors.forename: E
authors.initials: E
authors.lastname: Karg
authors.forename: I
authors.initials: I
authors.lastname: Németh
authors.forename: M
authors.initials: M
authors.lastname: Horanyi
authors.forename: M
authors.initials: M
authors.lastname: Inselt-Kovács
authors.forename: T
authors.initials: T
authors.lastname: Farkas
mesh_terms: D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000097:blood; D019803:Glutathione Disulfide / Q000097:blood; D005982:Glutathione Transferase / Q000097:blood; D006019:Glycolysis; D006801:Humans; D006814:Hungary; D008297:Male; D009410:Nerve Degeneration / Q000201:enzymology / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000235:genetics*; D009679:Nuclear Family; D010375:Pedigree; D010955:Plasmalogens / Q000378:metabolism; D014305:Triose-Phosphate Isomerase / Q000097:blood / Q000172:deficiency* / Q000235:genetics
chemical_list: D010955:Plasmalogens; D005982:Glutathione Transferase; D014305:Triose-Phosphate Isomerase; D005978:Glutathione; D019803:Glutathione Disulfide
vernacular_title: Déficiences en enzymes glycolytiques et neurodégénérescence.