title: Branched chain amino acids induce apoptosis in neural cells without mitochondrial membrane depolarization or cytochrome c release: implications for neurological impairment associated with maple syrup urine disease.
abstract: Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by a deficiency in branched chain alpha-keto acid dehydrogenase that can result in neurodegenerative sequelae in human infants. In the present study, increased concentrations of MSUD metabolites, in particular alpha-keto isocaproic acid, specifically induced apoptosis in glial and neuronal cells in culture. Apoptosis was associated with a reduction in cell respiration but without impairment of respiratory chain function, without early changes in mitochondrial membrane potential and without cytochrome c release into the cytosol. Significantly, alpha-keto isocaproic acid also triggered neuronal apoptosis in vivo after intracerebral injection into the developing rat brain. These findings suggest that MSUD neurodegeneration may result, at least in part, from an accumulation of branched chain amino acids and their alpha-keto acid derivatives that trigger apoptosis through a cytochrome c-independent pathway.
authors.affiliation: Weston Laboratory, Division of Paediatrics, Obstetrics, and Gynaecology, Imperial College of Science, Technology, and Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom.
authors.forename: P
authors.initials: P
authors.lastname: Jouvet
authors.forename: P
authors.initials: P
authors.lastname: Rustin
authors.forename: D L
authors.initials: DL
authors.lastname: Taylor
authors.forename: J M
authors.initials: JM
authors.lastname: Pocock
authors.forename: U
authors.initials: U
authors.lastname: Felderhoff-Mueser
authors.forename: N D
authors.initials: ND
authors.lastname: Mazarakis
authors.forename: C
authors.initials: C
authors.lastname: Sarraf
authors.forename: U
authors.initials: U
authors.lastname: Joashi
authors.forename: M
authors.initials: M
authors.lastname: Kozma
authors.forename: K
authors.initials: K
authors.lastname: Greenwood
authors.forename: A D
authors.initials: AD
authors.lastname: Edwards
authors.forename: H
authors.initials: H
authors.lastname: Mehmet
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D003574:Cytochrome c Group / Q000378:metabolism*; D053938:DNA Fragmentation; D004789:Enzyme Activation; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D007651:Keto Acids / Q000378:metabolism / Q000494:pharmacology; D007930:Leucine / Q000378:metabolism / Q000494:pharmacology; D008375:Maple Syrup Urine Disease / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000597:Amino Acids, Branched-Chain; D003574:Cytochrome c Group; D007651:Keto Acids; C013082:alpha-ketoisocaproic acid; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D007930:Leucine