Summary
In this short review we provide evidence that the branched-chain keto acids accumulating in the neurometabolic disorder maple syrup urine disease disturb rat cerebral cytoskeleton in a developmentally regulated manner. Alterations of protein phosphorylation leading to brain cytoskeletal misregulation and neural cell death caused by these metabolites are associated with energy deprivation, oxidative stress and excitotoxicity that may ultimately disrupt normal cell function and viability.
Similar content being viewed by others
References
Anesti V, Scorrano L (2006) The relationship between mitochondrial shape and function and the cytoskeleton. Biochim Biophys Acta 1757: 692–699.
Araújo P, Wassermann GF, Tallini K, et al (2001) Reduction of large neutral amino acid levels in plasma and brain of hyperleucinemic rats. Neurochem Int 38: 529–537.
Atkinson SJ, Hosford MA, Molitoris BA (2004) Mechanism of actin polymerization in cellular ATP depletion. J Biol Chem 279: 5194–5199.
Barschak AG, Sitta A, Deon M, et al (2006) Evidence that oxidative stress is increased in plasma from patients with maple syrup urine disease. Metab Brain Dis 21: 279–286.
Beaver CJ, Ji Q, Fischer QS, Daw NW (2001) Cyclic AMP-dependent protein kinase mediates ocular dominances shifts in cat visual cortex. Nat Neurosci 4: 159–163.
Ben-Ari Y (2002) Excitatory actions of GABA during development: the nature of the nurture. Nat Rev Neurosci 3: 728–739.
Ben-Ari Y, Khazipov R, Leinekugel X, Caillard O, Gaiarsa JL (1997) GABAA, NMDA and AMPA receptors: a developentally regulated ‘ménage a trois’ Trends Neurosci 20: 523–529.
Bernstein BW, Bamburg JR (2003) Actin-ATP hydrolysis is a major energy drain for neurons. J Neurosci 23: 1–6.
Bö L (2004) Grey matter pathology in early MS. In: Miller, DH, Filipi M, Thompson AJ, eds. MAGNIMS Clinically Isolated Syndrome Workshop, The National Hospital for Neurology and Neurosurgery, Queen Square, London, WCIN 3BG, 22–23. Jan., MS NMR Research, Unit, Department of Neuroinflammation.
Butterfield DA (2002) Amyloid beta-peptide (1–42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer’s disease brain. A review. Free Radic Res 36: 1307–1313.
Branco T, Meirelles R, Bevilaqua da Rocha B, de Mattos-Dutra Â, Wajner M, Pessoa-Pureur R (2000) Alpha-ketoisocaproate increases the in vitro 32P incorporation into intermediate filaments in cerebral cortex of rats. NeuroReport 11: 3545–3550.
Bridi R, Araldi J, Sgarbi MB, et al (2003) Induction of oxidative stress in rat brain by metabolites accumulating in maple syrup urine disease. Int J Dev Neurosci 21: 327–332.
Bridi R, Braun CA, Zorzi GK, et al (2005) Alpha-keto acids accumulating in maple syrup urine disease stimulate lipid peroxidation and reduce antioxidant defences in cerebral cortex from young rats. Metab Brain Dis 20: 155–167.
Brismar J, Aqeel A, Brismar G, Coates R, Gascon G, Ozand P (1990) Maple syrup urine disease: findings on CT and MR scans of the brain in 10 infants. Am J Neuroradiol 11: 1219–1228.
Chang L, Goldman RD (2004) Intermediate filaments mediate cytoskeletal crosstalk. Nat Rev Mol Cell Biol 5: 601–613.
Chiasson K, Lahaie-Collins V, Bournival J, Delapierre B, Gelinas S, Martinoli MG (2006) Oxidative stress and 17-alpha- and 17-beta-estradiol modulate neurofialments differently. J Mol Neurosci 30: 297–310.
Choi DW (1988) Glutamate neurotoxicity and disease of the nervous system. Neuron 1: 623–634.
Chuang DT, Shih VE (2001) Maple syrup urine disease (branched-chain ketoaciduria). In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc. eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 1971–2005.
Cotrina ML, Lin JH, Nedergaard M (1998) Cytoskeletal assembly and ATP release regulate astrocytic calcium signaling. J Neurosci 18: 8794–8804.
Daniel JL, Molish IR, Robkin L, Holmsen H (1986) Nucleotide exchange between cytosolic ATP and F-actin-bound ADP may be a major energy-utilizing process in unstimulated platelets. Eur J Biochem 156: 677–684.
Danner DJ, Elsas JL (1989) Disorders of branched chain amino acid and keto acid metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill, 671–692.
Dawson TM, Dawson VL, Snyder SH (1992) A novel neuronal messenger molecule in brain: the free radical nitric oxide. Ann Neurol 32: 297–311.
Diprospero NA, Chen E-Y, Charles V, Plomann M, Kordower JH, Tangle DA (2004) Early changes in Huntington’s disease patient brains involve alterations in cytoskeletal and synaptic elements. J Neurocytol 33: 517–533.
Dodd PR, Williams SH, Gundlach AL, et al (1992) Glutamate and gamma-aminobutyric acid neurotransmitter systems in the acute phase of maple syrup urine disease and citrullinemia encephalopathies in newborn calves. J Neurochem 59: 582–590.
Duan S, Anderson CM, Stein BA, Swanson RA (1999) Glutamate induces rapid up regulation of astrocyte glutamate transport and cell-surface expression of GLAST. J Neurosci 19: 10193–10200.
Eng LF, Lee YL (1995) Intermediate filaments in astrocytes. In: Ransom BR and Akettenmann H, eds. Neuroglial Cells. New York: Oxford University Press, 650–667.
Fontella FU, Pulrolnik V, Gassen E, et al (2000) Propionic and L-methylmalonic acids induce oxidative stress in brain of young rats. NeuroReport 11: 541–544.
Fontella FU, Gassen E, Pulrolnik V, et al (2002) Stimulation of lipid peroxidation in vitro in rat brain by the metabolites accumulating in maple syrup urine disease. Metab Brain Dis 17: 47–54.
Freitas M de, Mattos-Dutra  de, Schroder N, Wannmacher CMD, Pessoa-Pureur R (1997) Effect of hyperphenylalaninemia chemically induced on in vitro incorporation of 32P into cytoskeletal proteins from cerebral cortex of developing rats. Exp Neurol 143: 188–195.
Funchal C, de Lima Pelaez P, Oliveira Loureiro S, et al (2002) α-Ketoisocaproic acid regulates phosphorylation of intermediate filaments in postnatal rat cortical slices through ionotropic glutamatergic receptors. Dev Brain Res 139: 267–276.
Funchal C, Dall Bello Pessutto F, Vieira de Almeida LM, et al (2004a) α-Keto-β-methylvaleric acid increases the in vitro phosphorylation of intermediate filaments in cerebral cortex of young rats through the GABAergic system. J Neurol Sci 217: 17–24.
Funchal C, Gottfried C, Vieira de Almeida LM, Wajner M, Pessoa-Pureur R (2004b) Evidence that the branched-chain α-keto acids accumulating in maple syrup urine disease induce morphological alterations and death in cultured astrocytes from rat cerebral cortex. Glia 48: 230–240.
Funchal C, Rosa AM, Wajner M, Wofchuk S, Pessoa-Pureur R (2004c) Reduction of glutamate uptake in cerebral cortex of developing rats by the branched chain α-keto acids accumulating in maple syrup urine disease. Neurochem Res 29: 747–753.
Funchal C, Zamoner A, Quincozes dos Santos A, Oliveira Loureiro S, Wajner M, Pessoa-Pureur R (2005a) Alpha-ketoisocaproic acid increases phosphorylation of intermediate filament proteins from rat cerebral cortex by mechanisms involving Ca2+ and cAMP. Neurochem Res 30: 1139–1146.
Funchal C, Quincozes dos Santos A, Jacques-Silva MC, et al (2005b) Branched-chain α-keto acids accumulating in maple syrup urine disease induce reorganization of phosphorylated GFAP in C6-gioma cells. Metab Brain Dis 20: 205–217.
Funchal C, Zamoner A, Quincozes dos Santos A, et al (2005c) Evidence that intracellular Ca2+ mediates the effect of α-ketoisocaproic acid on the phosphorylating system of cytoskeletal proteins from cerebral cortex of immature rats. J Neurol Sci 238: 75–82.
Funchal C, Gottfried C, Vieira de Almeida LM, Quincozes dos Santos A, Wajner M, Pessoa-Pureur R (2005d) 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. Cel Mol Neurobiol 25: 851–867.
Funchal C, Schuck PF, Quincozes dos Santos A, et al (2006a) Creatine and antioxidant treatment prevent the inhibition of creatine kinase activity and the morphological alterations of C6 glioma cells induced by the branched-chain α-keto acids accumulating in maple syrup urine disease. Cell Mol Neurobiol 26: 67–79.
Funchal C, Latini A, Quincozes dos Santos A, et al (2006b) Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain keto acids accumulating in maple syrup urine disease. Neurochem Int 49: 640–650.
Gaiarsa JJ, Caillard O, Ben-Ari Y (2002) Long-term plasticity at GABAergic and glycinergic synapses: mechanisms and functional significance. Trends Neurosci 25: 564–570.
Goedert M (1998) Filamentous nerve cell inclusions in neurodegenerative diseases. Curr Opin Neurobiol 8: 619–632.
Gourlay CW, Ayscough KR (2005) The actin cytoskeleton: a key regulator of apoptosis and ageing? Nat Rev Mol Cell Biol 6: 583–589.
Greenamyre JT, Higgins DS, Young AB, Penney JB (1990) Regional ontogeny of a unique glutamate recognition site in rat brain: an autoradiographic study. Int J Dev Neurosci 8: 437–445.
Ha JS, Kim TK, Eun BL, et al (2004) Maple syrup urine disease encephalopathy: a follow-up study in the acute stage using diffusion-weighted MRI. Pediar Radiol 34: 163–166.
Halestrap A, Brand MD, Denton RM (1974) Inhibition of mitochondrial pyruvate transport by phenylpyruvate and-ketoisocaproate. Biochim Biophys Acta 367: 102–108.
Hedreen JC, Koliatsos VE (1994) Phosphorylated neurofilaments in neuronal perikarya and dendrites in human brain following axonal damage. J Neuropathol Exp Neurol 53: 663–671.
Herrmann H, Aebi U (2004) Intermediate filament: molecular structure, assembly mechanism, and integration into functionally distinct intracellular scaffolds. Annu Rev Biochem 73: 749–789.
Hoffman PN, Cleveland DW, Griffin JW, Landes PW, Cowan NJ, Price DL (1987) Neurofilament gene expression: a major determinant of axonal caliber. Proc Natl Acad Sci USA 84: 3472–3476.
Hollenbeck PJ, Saxton WM (2005) The axonal transport of mitochondria. J Cell Sci 118: 5411–5419.
Howell RK, Lee M (1963) Influence of alpha-ketoacids on the respiration of brain in vitro. Proc Soc Exp Biol Med 113: 660–663.
Hugon J, Vallat JM (1990) Abnormal distribution of phosphorylated neurofilaments in neuronal degeneration induced by kainic acid. Neurosci Lett 119: 45–48.
Jensen F (2002) The role of glutamate receptor maturation in perinatal seizures in brain injury. Int J Dev Neurosci 20: 339–347.
Jouvet P, Rustin P, Taylor DL, et al (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. Mol Biol Cell 11: 1919–1932.
Julien JP (1999) Neurofilament functions in health and disease. Curr Opin Neurobiol 9: 554–560.
Julien JP, Mushynski WE (1998) Neurofilaments in health and disease. Prog Nucleic Acid Res Mol Biol 61: 1–23.
Kamei A, Takashima S, Chan F, Becker LE (1992) Abnormal dendritic development in maple syrup urine disease. Pediatr Neurol 8: 145.
Koliatsos VE, Applegate MD, Kitt CA, Walker LC, De Long MR, Price DL (1989) Aberrant phosphorylation of neurofilaments accompanies transmitter-related changes in rat septal neurons following transection of the fimbria-fornix. Brain Res 482: 205–218.
Lascola CD, Nelson DJ, Kraig RP (1998) Cytoskeletal actin gates a Cl~ channel in neocortical astrocytes. J Neurosci 18: 1679–1692.
Lasek RJ, Black MM, eds. (1988) Intrinsic Determinants of Neuronal Form and Function, (Neurology and Neurobiology, vol. 37). New York: Alan R Liss.
Lee MK, Cleveland DW (1996) Neuronal intermediate filaments. Annu Rev Neurosci 19: 187–217.
Mattos-Dutra  de, Meirelles R, Bevilaqua da Rocha B, et al (2000) Methylmalonic and propionic acids increase the in vitro incorporation of 32P into cytoskeletal proteins from cerebral cortex of young rats through NMDA glutamate receptors. Brain Res 856: 111–118.
Miller CCJ, Ackerley S, Brownless J, Grierson AJ, Jacobsen NJO, Thornhill P (2002) Axonal transport of neurofilaments in normal and disease states. Cell Mol Life Sci 59: 323–330.
Nixon RA (1993) The regulation of neurofilament protein dynamics by phosphorylation clues to neurofibrillary pathobiology. Brain Pathol 3: 29–38.
Nixon RA, Paskevich PA, Sihag RK, Thayer CY (1994) Phosphorylation on carboxyl-terminus domains of neurofilament proteins in retinal ganglion-cell neurons in vivo influences on regional neurofilament accumulation, interneurofilament spacing, and axon caliber. J Cell Biol 126: 1031–1046.
O’Callaghan JP (1994) A potential role for altered protein phosphorylation in the mediation of developmental neurotoxicity. Neuro Toxicol 15: 29–40.
Pessoa-Pureur R, Funchal C, de Lima Pelaez P, et al (2002) Effect of the branched-chain alpha-ketoacids accumulating in maple syrup urine disease on the high molecular weight neurofilament subunit (NF-H) in rat cerebral cortex. Metab Brain Dis 17: 65–75.
Petzold A (2005) Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss. J Neurol Sci 233: 183–198.
Pilla C, Cardozo RFD, Dutra CS, Wyse ATS, Wajner M, Wannmacher CMD (2003) Effect of leucine administration on creatine kinase activity in rat brain. Metab Brain Dis 18: 17–25.
Pollard H, Khrestchatisky M, Moreau J, Ben Ari Y (1993) Transient expression of the NR2C subunit of the NMDA receptor in developing rat brain. NeuroReport 4: 411–414.
Revenu C, Athman R, Robine S, Louvard D (2004) The co-workers of actin filaments: from cell structures to signals. Nat Rev Mol Cell Biol 5: 1–12.
Ridley AJ (2001) Rho proteins: linking signaling with membrane. Traffic 2: 303–310.
Righini A, Raminhi LA, Parini R, Triulzi F, Mosca F (2003) Water apparent diffusion coefficient and T2 changes in the acute stage of maple syrup urine disease: evidence of intramyelinic and vasogenic-interstitial edema. J Neuroimaging 13: 162–165.
Sanderson C, Murphy S (1981) Glutamate binding in the rat cerebral cortex during ontogeny. Brain Res 254: 329–339.
Schmidt, RE, Beaudet LN, Plurad SB, Dorsey DA (1997) Axonal cytoskeketal pathology in aged and diabetic human sympathetic autonomic ganglia. Brain Res 769: 375–383.
Schönberger S, Schweiger B, Schwahn B, Schwarz M, Wendel U (2004) Dysmyelination in the brain of adolescents and young adults with maple syrup urine disease. Mol Genet Metab 82: 69–75.
Sergeeva MM, Ubl JJ, Reiser G (2000) Disruption of actin cytoskeleton in cultured rat astrocytes suppresses ATP- and bradykinin induced (Ca2+)i oscillations by reducing the coupling eficiency between Ca2+ release, capacitative Ca2+ entry, and store refilling. Neuroscience 97: 765–769.
Sgaravatti AM, Rosa RB, Schuck PF, et al (2003) Inhibition of energy metabolism by the α-keto acids accumulating in maple syrup urine disease. Biochem Biophys Acta 1639: 232–238.
Shea TB, Zheng YL, Ortiz D, Pant HC (2004) Cyclin-dependent kinase 5 increases perikaryal neurofilament phosphorylation and inhibits neurofilament axonal transport in response to oxidative stress. J Neurosci Res 76: 795–800.
Silberman J, Dancis J, Feijin I (1961) Neuropathological observations in maple syrup urine disease. Arch Neurol 15: 351.
Snyderman SE, Norton PM, Roitman E (1964) Maple syrup urine disease with particular reference to diet therapy. Pediatrics 34: 454–472.
Strelkov SV, Herrmann H, Aebi U (2003) Molecular architecture of intermediate filaments. Bioessays 25: 243–251.
Tashian RE (1961) Inhibition of brain glutamic acid decarboxylase by phenylalanine, valine, and leucine derivatives: a suggestion concerning the etiology of the neurological defect in phenylketonuria and branched-chain ketonuria. Metabolism 10: 393–402.
Tavares, RG, Santos CES, Tasca CI, Wajner M, Souza DO, Dutra-Filho CS (2000) Inhibition of glutamate uptake into synaptic vesicles of rat brain by the metabolites accumulating in maple syrup urine disease. J Neurol Sci 181: 44–49.
Tremblay E, Roisin MP, Represa A, Charriaut-Marlangue C, Ben Ari Y (1988) Transient increased density of NMDA binding sites in the developing rat hippocampus. Brain Res 461: 393–396.
Trout JJ, Koenig H, Goldstone AD, Iqbal Z, Ju CY, Siddiqui F (1993) N-Methyl-d-aspartate receptor excitotoxicity involves activation of polyamine synthesis: protection by α-difluoromethylornithine. J Neurochem 60: 352–355.
Vieira de Almeida LM, Funchal C, de Lima Pelaez P, et al (2003) Effect of propionic and methylmalonic acids on the in vitro phosphorylation of intermediate filaments from cerebral cortex of rats during development. Metab Brain Dis 18: 207–219.
Vieira de Almeida LM, Funchal C, Gottfried C, Wajner M, Pessoa Pureur R (2006) Propionic acid induces cytoskeletal alterations in cultured astrocytes from rat cerebral cortex. Metab Brain Dis 21: 49–60.
Wadsworth P (1999) Regional regulation of microtubule dynamics in polarized, motile cells. Cell Motil Cytoskeleton 42: 48–59.
Wang C, Jensen FE (1996) Age dependence of NMDA receptor involvement in epileptiform activity in rat hippocampal slices. Epilepsy Res 23: 105–113.
Watanabe T, Noritake J, Kaibuchi K (2005) Regulation of microtubules in cell migration. Trends Cell Biol 15: 76–83.
Watson DF, Griffin JW, Fittro KP, Hoffman PN (1989) Phosphorylation-dependent immunoreactivity of neurofilaments increases during axonal maturation and β,β’-iminodipropionitrile intoxication. J Neurochem 53: 1818–1829.
Watson DF, Fittro KP, Hoffman PN, Griffin JW (1991) Phosphorylation-related immunoreactivity and the rate of transport of neurofilaments in chronic 2,5-hexanedione intoxication. Brain Res 539: 103–109.
Waxman SG, Kocsis JD, Stys PK, eds. (1995) The Axon: Structure, Function and Pathophysiology. New York: Oxford University Press.
Yudkoff M, Daikhin Y, Nelson D, Nissim I, Erecinska M (1996) Neuronal metabolism of branched-chain amino acids: flux through the aminotransferase pathway in synaptosomes. J Neurochem 66: 2136–2145.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicating editor: Michael Gibson
Competing interests: None declared
Rights and permissions
About this article
Cite this article
Pessoa-Pureur, R., Wajner, M. Cytoskeleton as a potential target in the neuropathology of maple syrup urine disease: Insight from animal studies. J Inherit Metab Dis 30, 664–672 (2007). https://doi.org/10.1007/s10545-007-0562-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10545-007-0562-6