title: NMDA Receptors and Oxidative Stress Induced by the Major Metabolites Accumulating in HMG Lyase Deficiency Mediate Hypophosphorylation of Cytoskeletal Proteins in Brain From Adolescent Rats: Potential Mechanisms Contributing to the Neuropathology of This Disease.
abstract: Neurological symptoms and cerebral abnormalities are commonly observed in patients with 3-hydroxy-3-methylglutaryl-CoA lyase (HMG lyase) deficiency, which is biochemically characterized by predominant tissue accumulation of 3-hydroxy-3-methylglutaric (HMG), 3-methylglutaric (MGA), and 3-methylglutaconic (MGT) acids. Since the pathogenesis of this disease is poorly known, the present study evaluated the effects of these compounds on the cytoskeleton phosphorylating system in rat brain. HMG, MGA, and MGT caused hypophosphorylation of glial fibrillary acidic protein (GFAP) and of the neurofilament subunits NFL, NFM, and NFH. HMG-induced hypophosphorylation was mediated by inhibiting the cAMP-dependent protein kinase (PKA) on Ser55 residue of NFL and c-Jun kinase (JNK) by acting on KSP repeats of NFM and NFH subunits. We also evidenced that the subunit NR2B of NMDA receptor and Ca(2+) was involved in HMG-elicited hypophosphorylation of cytoskeletal proteins. Furthermore, the antioxidants L-NAME and TROLOX fully prevented both the hypophosphorylation and the inhibition of PKA and JNK caused by HMG, suggesting that oxidative damage may underlie these effects. These findings indicate that the main metabolites accumulating in HMG lyase deficiency provoke hypophosphorylation of cytoskeleton neural proteins with the involvement of NMDA receptors, Ca(2+), and reactive species. It is presumed that these alterations may contribute to the neuropathology of this disease.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600 anexo, Porto Alegre, RS, CEP 90035-003, Brazil.
authors.forename: Carolina Gonçalves
authors.initials: CG
authors.lastname: Fernandes
authors.forename: Paula
authors.initials: P
authors.lastname: Pierozan
authors.forename: Gilberto Machado
authors.initials: GM
authors.lastname: Soares
authors.forename: Fernanda
authors.initials: F
authors.lastname: Ferreira
authors.forename: Ângela
authors.initials: Â
authors.lastname: Zanatta
authors.forename: Alexandre Umpierrez
authors.initials: AU
authors.lastname: Amaral
authors.forename: Clarissa Günther
authors.initials: CG
authors.lastname: Borges
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
authors.forename: Regina
authors.initials: R
authors.lastname: Pessoa-Pureur
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000172:deficiency* / Q000378:metabolism; D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: D003598:Cytoskeletal Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D000101:Acetyl-CoA C-Acetyltransferase; D002118:Calcium