Vol. 11, Issue 5, 1919-1932, May 2000

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

Philippe Jouvet,^* Pierre Rustin, Deanna L. Taylor,^* Jennifer M. Pocock, Ursula Felderhoff-Mueser,^* Nicholas D. Mazarakis,^*§ Catherine Sarraf, Umesh Joashi,^* Mary Kozma,^* Kirsty Greenwood,^* A. David Edwards,^* and Huseyin Mehmet^*¶

 ^*Weston Laboratory, Division of Paediatrics, Obstetrics, and Gynaecology, and  Division of Investigative Sciences, Imperial College of Science, Technology, and Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom;  Unité de Recherches sur les Handicaps Génétiques de l'Enfant, Institut National de la Santé et de la Recherche Médicale U393, Hôpital Necker Enfants Malades, 75743 Paris Cedex 15, France; and  Department of Neurochemistry, Institute of Neurology, University College London, London WC1N 1PJ, United Kingdom

Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by a deficiency in branched chain -keto acid dehydrogenase that can result in neurodegenerative sequelae in human infants. In the present study, increased concentrations of MSUD metabolites, in particular -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, -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 -keto acid derivatives that trigger apoptosis through a cytochrome c-independent pathway.