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

Autor(es)

Fernandes, Carolina Goncalves ^[1] ; Pierozan, Paula ^[1] ; Soares, Gilberto Machado ^[1] ; Ferreira, Fernanda ^[1] ; Zanatta, Angela ^[1] ; Amaral, Alexandre Umpierrez ^[1] ; Borges, Clarissa Guenther ^[1] ; Wajner, Moacir ^{[1, 2]} ; Pessoa-Pureur, Regina ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Rio Grande do Sul, Inst Ciencias Basicas Saude, Dept Bioquim, BR-90035003 Porto Alegre, RS - Brazil

^[2] Hosp Clin Porto Alegre, Serv Genet Med, Porto Alegre, RS - Brazil

• Tipo de documento: Artigo Científico
• Fonte: NEUROTOXICITY RESEARCH; v. 28, n. 3, p. 239-252, OCT 2015.
• Citações Web of Science: 6

Resumo

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 Ca2+ 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, Ca2+, and reactive species. It is presumed that these alterations may contribute to the neuropathology of this disease. (AU)

• Processo FAPESP: 11/50400-0 - Metabolismo energético, estado redox e funcionalidade mitocondrial na morte celular e em desordens cardiometabólicas e neurodegenerativas
• Beneficiário: Aníbal Eugênio Vercesi
• Modalidade de apoio: Auxílio à Pesquisa - Temático