Morphological alterations and cell death provoked by the branched-chain α-amino acids accumulating in maple syrup urine disease in astrocytes from rat cerebral cortex

Cláudia Funchal, Carmem Gottfried, Lúcia Maria Vieira De Almeida, André Quincozes Dos Santos, Moacir Wajner, Regina Pessoa-Pureur*

*Corresponding author for this work

Research output: Contribution to journalArticle

9 Scopus citations

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 appearence 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.

Original languageEnglish (US)
Pages (from-to)851-867
Number of pages17
JournalCellular and Molecular Neurobiology
Volume25
Issue number5
DOIs
StatePublished - Aug 1 2005

Keywords

  • Actin
  • Branched-chain amino acids
  • Creatine
  • Cytoskeleton
  • Lysophosphatidic acid
  • Maple syrup urine disease

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Biochemistry
  • Cell Biology
  • Genetics

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