Evidence that the branched-chain alpha-keto acids accumulating in maple syrup urine disease induce morphological alterations and death in cultured astrocytes from rat cerebral cortex

Glia
Cláudia FunchalRegina Pessoa-Pureur

Abstract

Severe neurological symptoms, cerebral edema, and atrophy are common features of the inherited metabolic disorder maple syrup urine disease (MSUD). However, the pathomechanisms involved in the neuropathology of this disease are not well established. In this study, we investigated the effects of the branched-chain keto acids (BCKA) alpha-ketoisocaproic (KIC), alpha-ketoisovaleric (KIV), and alpha-keto-beta-methylvaleric (KMV), which accumulate in MSUD, on astrocyte morphology and cytoskeleton reorganization. Cultured astrocytes from cerebral cortex of neonatal rats were exposed to various concentrations of the BCKA and cell morphology was studied. We observed that these cells changed their usual polygonal morphology when exposed to BCKA, leading to the appearance of fusiform or process-bearing cells. Furthermore, longer exposures to the BCKA elicited cell death at all concentrations studied, attaining massive death at the highest concentrations. Immunocytochemistry with anti-actin or anti-GFAP antibodies revealed that the BCKA induced reorganization of actin and GFAP cytoskeleton. In addition, astrocytes treated with lysophosphatidic acid, an upstream activator of the RhoA GTPase pathway, totally prevented the morphological alte...Continue Reading

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Citations

Jun 19, 2007·Journal of Inherited Metabolic Disease·R Pessoa-Pureur, M Wajner
Mar 6, 2007·Cellular and Molecular Neurobiology·Ariane ZamonerRegina Pessoa-Pureur
Apr 5, 2013·PloS One·Débora Guerini SouzaAndré Quincozes-Santos
Jun 3, 2014·Orphanet Journal of Rare Diseases·Kara R VogelK Michael Gibson
Jun 15, 2014·Metabolism: Clinical and Experimental·Janne M StrandLars Eide
Dec 19, 2012·Seminars in Pediatric Neurology·Andrea L Gropman
Feb 24, 2007·International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience·Priscila de Lima PelaezRegina Pessoa-Pureur
May 21, 2013·Analytical Biochemistry·Kristine C OlsonChristopher J Lynch
Sep 15, 2017·Journal of Inherited Metabolic Disease·Marie-Thérèse Abi-WardéPascale de Lonlay

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