title: Morphological alterations and cell death provoked by the branched-chain alpha-amino acids accumulating in maple syrup urine disease in astrocytes from rat cerebral cortex.
abstract: 1. Maple syrup urine disease (MSUD) is an inherited metabolic disorder predominantly characterized by neurological dysfunction and cerebral atrophy whose patophysiology is poorly known. 2. We investigated here whether the branched-chain amino acids (BCAA) leucine (Leu), isoleucine (Ile) and valine (Val), which are the biochemical hallmark of this disorder, could alter astrocyte morphology and cytoskeleton reorganization by exposing cultured astrocytes from cerebral cortex of neonatal rats to various concentrations of the amino acids. A change of cell morphology from the usual polygonal to the appearance of fusiform or process-bearing cells was caused by the BCAA. Cell death was also observed when astrocytes were incubated in the presence of BCAA for longer periods. 3. Val-treated astrocytes presented the most dramatic morphological alterations. Immunocytochemistry with anti-actin and anti-GFAP antibodies revealed that all BCAA induced reorganization of actin and GFAP cytoskeleton. In addition, lysophosphatidic acid, an activator of RhoA GTPase pathway, was able to totally prevent the morphological alterations and cytoskeletal reorganization induced by Val, indicating that the RhoA signaling pathway was involved in these effects. 4. Furthermore, creatine attenuated the morphological alterations provoked by the BCAA, the protection being more pronounced for Val, suggesting that impairment of energy homeostasis is partially involved in BCAA cytotoxic action. The data indicate that the BCAA accumulating in MSUD are toxic to astrocyte cells, a fact that may be related to the pathogenesis of the neurological dysfunction of MSUD patients.
authors.affiliation: Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Rua Ramiro Barcelos 2600 anexo, 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Cláudia
authors.initials: C
authors.lastname: Funchal
authors.forename: Carmem
authors.initials: C
authors.lastname: Gottfried
authors.forename: Lúcia Maria Vieira
authors.initials: LM
authors.lastname: de Almeida
authors.forename: André Quincozes
authors.initials: AQ
authors.lastname: dos Santos
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
authors.forename: Regina
authors.initials: R
authors.lastname: Pessoa-Pureur
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000493:pharmacokinetics*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D016923:Cell Death / Q000502:physiology*; D002467:Cell Nucleus / Q000473:pathology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003401:Creatine / Q000494:pharmacology; D007150:Immunohistochemistry; D008246:Lysophospholipids / Q000494:pharmacology; D008375:Maple Syrup Urine Disease / Q000378:metabolism / Q000473:pathology*; D051381:Rats
chemical_list: D000597:Amino Acids, Branched-Chain; D008246:Lysophospholipids; D003401:Creatine; C032881:lysophosphatidic acid