Abstract
The Neuronal Ceroid Lipofuscinoses (NCL) are a group of fatal inherited neurodegenerative diseases in humans distinguished by a common clinical pathology, characterized by the accumulation of storage body material in cells and gross brain atrophy. In this study, metabolic changes in three NCL mouse models were examined looking for pathways correlated with neurodegeneration. Two mouse models; motor neuron degeneration (mnd) mouse and a variant model of late infantile NCL, termed the neuronal ceroid lipofuscinosis (nclf) mouse were investigated experimentally. Both models exhibit a characteristic accumulation of autofluorescent lipopigment in neuronal and non neuronal cells. The NMR profiles derived from extracts of the cortex and cerebellum from mnd and nclf mice were distinguished according to disease/wildtype status. In particular, a perturbation in glutamine and glutamate metabolism, and a decrease in γ-amino butyric acid (GABA) in the cerebellum and cortices of mnd (adolescent mice) and nclf mice relative to wildtype at all ages were detected. Our results were compared to the Cln3 mouse model of NCL. The metabolism of mnd mice resembled older (6 month) Cln3 mice, where the disease is relatively advanced, while the metabolism of nclf mice was more akin to younger (1-2 months) Cln3 mice, where the disease is in its early stages of progression. Overall, our results allowed the identification of metabolic traits common to all NCL subtypes for the three animal models.
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Behrens PF, Franz P, Woodman B, Lindenberg KS, Landwehrmeyer GB (2002) Impaired glutamate transport and glutamate-glutamine cycling: downstream effects of the Huntington mutation. Brain 125(Pt 8):1908–1922
Bible E, Gupta P, Hofmann SL, Cooper JD (2004) Regional and cellular neuropathology in the palmitoyl protein thioesterase-1 null mutant mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis 16(2):346–359
Bronson RT, Donahue LR, Johnson KR, Tanner A, Lane PW, Faust JR (1998) Neuronal ceroid lipofuscinosis (nclf), a new disorder of the mouse linked to chromosome 9. Am J Med Genet 77(4):289–297
Burbaeva G, Boksha IS, Turishcheva MS, Vorobyeva EA, Savushkina OK, Tereshkina EB (2003) Glutamine synthetase and glutamate dehydrogenase in the prefrontal cortex of patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 27(4):675–680
Chakraborty G, Mekala P, Yahya D, Wu G, Ledeen RW (2001) Intraneuronal N-acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase. J Neurochem 78(4):736–745
Chan CH, Ramirez-Montealegre D, Pearce DA (2009) Altered arginine metabolism in the central nervous system (CNS) of the Cln3(-/-) mouse model of juvenile Batten disease. Neuropath Appl Neuro 35(2):189–207
Chang B, Bronson RT, Hawes NL, Roderick TH, Peng C, Hageman GS, Heckenlively JR (1994) Retinal degeneration in motor neuron degeneration: a mouse model of ceroid lipofuscinosis. Invest Ophthalmol Vis Sci 35(3):1071–1076
Chattopadhyay S, Ito M, Cooper JD, Brooks AI, Curran TM, Powers JM, Pearce DA (2002) An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease. Hum Mol Genet 11(12):1421–1431
Cooper JD (2003) Progress towards understanding the neurobiology of Batten disease or neuronal ceroid lipofuscinosis. Curr Opin Neurol 16(2):121–128
Cooper JD, Messer A, Feng AK, Chua-Couzens J, Mobley WC (1999) Apparent loss and hypertrophy of interneurons in a mouse model of neuronal ceroid lipofuscinosis: evidence for partial response to insulin-like growth factor-1 treatment. J Neurosci 19(7):2556–2567
Eriksson L, Johansson E, Kettaneh-Wold N, Wold S (1999) Introduction to multi- and megavariate data analysis using projection methods (PCA and PLS). Umetrics, Umea
Gachet Y, Codlin S, Hyams JS, Mole SE (2005) btn1, the Schizosaccharomyces pombe homologue of the human Batten disease gene CLN3, regulates vacuole homeostasis. J Cell Sci 118(Pt 23):5525–5536
Goebel HH, Sharp JD (1998) The neuronal ceroid-lipofuscinoses. Recent advances. Brain Pathol 8(1):151–162
Govindaraju V, Young K, Maudsley AA (2000) Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed 13(3):129–153
Griffin JL, Muller D, Woograsingh R, Jowatt V, Hindmarsh A, Nicholson JK, Martin JE (2002) Vitamin E deficiency and metabolic deficits in neuronal ceroid lipofuscinosis described by bioinformatics. Physiol Genomics 11(3):195–203
Jackson JE (1991) A user’s guide to principal components. Wiley, New York
Jarvela I, Sainio M, Rantamaki T, Olkkonen VM, Carpen O, Peltonen L, Jalanko A (1998) Biosynthesis and intracellular targeting of the CLN3 protein defective in Batten disease. Hum Mol Genet 7(1):85–90
Kakela R, Somerharju P, Tyynela J (2003) Analysis of phospholipid molecular species in brains from patients with infantile and juvenile neuronal-ceroid lipofuscinosis using liquid chromatography-electrospray ionization mass spectrometry. J Neurochem 84(5):1051–1065
Katz ML, Shibuya H, Liu PC, Kaur S, Gao CL, Johnson GS (1999) A mouse gene knockout model for juvenile ceroid-lipofuscinosis (Batten disease). J Neurosci Res 57(4):551–556
Kim Y, Ramirez-Montealegre D, Pearce DA (2003) A role in vacuolar arginine transport for yeast Btn1p and for human CLN3, the protein defective in Batten disease. Proc Natl Acad Sci USA 100(26):15458–15462
Kyttala A, Ihrke G, Vesa J, Schell MJ, Luzio JP (2004) Two motifs target Batten disease protein CLN3 to lysosomes in transfected nonneuronal and neuronal cells. Mol Biol Cell 15(3):1313–1323
Le Belle JE, Harris NG, Williams SR, Bhakoo KK (2002) A comparison of cell and tissue extraction techniques using high-resolution 1H-NMR spectroscopy. NMR Biomed 15(1):37–44
Lee RL, Johnson KR, Lerner TJ (1996) Isolation and chromosomal mapping of a mouse homolog of the Batten disease gene CLN3. Genomics 35(3):617–619
Lindon JC, Nicholson JK, Everett JR (1999) NMR spectroscopy of biofluids. In: Annual Reports on Nmr Spectroscopy, Vol 38, vol 38. Annual Reports on Nmr Spectroscopy, pp 1–88
Luiro K, Kopra O, Lehtovirta M, Jalanko A (2001) CLN3 protein is targeted to neuronal synapses but excluded from synaptic vesicles: new clues to Batten disease. Hum Mol Genet 10(19):2123–2131
Luiro K, Yliannala K, Ahtiainen L, Maunu H, Jarvela I, Kyttala A, Jalanko A (2004) Interconnections of CLN3, Hook1 and Rab proteins link Batten disease to defects in the endocytic pathway. Hum Mol Genet 13(23):3017–3027
Macura S, Huang Y (1981) Two-dimensional chemical exchange and cross-relaxation spectroscopy of coupled nuclear spins. J Magn Reson 43(2):259–281
Mann DM, Yates PO, Stamp JE (1978) The relationship between lipofuscin pigment and ageing in the human nervous system. J Neurol Sci 37(1–2):83–93
Mitchison HM, Bernard DJ, Greene ND, Cooper JD, Junaid MA, Pullarkat RK, de Vos N, Breuning MH, Owens JW, Mobley WC, Gardiner RM, Lake BD, Taschner PE, Nussbaum RL (1999) Targeted disruption of the Cln3 gene provides a mouse model for Batten disease. The Batten Mouse Model Consortium [corrected]. Neurobiol Dis 6(5):321–334
Mitchison HM, Lim MJ, Cooper JD (2004) Selectivity and types of cell death in the neuronal ceroid lipofuscinoses. Brain Pathol 14(1):86–96
Oswald MJ, Kay GW, Palmer DN (2001) Changes in GABAergic neuron distribution in situ and in neuron cultures in ovine (OCL6) Batten disease. Eur J Paediatr Neurol 5(Suppl A):135–142
Pardo CA, Rabin BA, Palmer DN, Price DL (1994) Accumulation of the adenosine triphosphate synthase subunit C in the mnd mutant mouse. A model for neuronal ceroid lipofuscinosis. Am J Pathol 144(4):829–835
Pearce DA, Ferea T, Nosel SA, Das B, Sherman F (1999) Action of BTN1, the yeast orthologue of the gene mutated in Batten disease. Nat Genet 22(1):55–58
Pears MR, Cooper JD, Mitchison HM, Mortishire-Smith RJ, Pearce DA, Griffin JL (2005) High resolution 1H NMR-based metabolomics indicates a neurotransmitter cycling deficit in cerebral tissue from a mouse model of Batten disease. J Biol Chem 280(52):42508–42514
Petroff OA, Errante LD, Rothman DL, Kim JH, Spencer DD (2002) Glutamate-glutamine cycling in the epileptic human hippocampus. Epilepsia 43(7):703–710
Pontikis CC, Cella CV, Parihar N, Lim MJ, Chakrabarti S, Mitchison HM, Mobley WC, Rezaie P, Pearce DA, Cooper JD (2004) Late onset neurodegeneration in the Cln3-/- mouse model of juvenile neuronal ceroid lipofuscinosis is preceded by low level glial activation. Brain Res 1023(2):231–242
Ramirez-Montealegre D, Pearce DA (2005) Defective lysosomal arginine transport in juvenile Batten disease. Hum Mol Genet 14(23):3759–3773
Ranta S, Zhang Y, Ross B, Lonka L, Takkunen E, Messer A, Sharp J, Wheeler R, Kusumi K, Mole S, Liu W, Soares MB, Bonaldo MF, Hirvasniemi A, de la Chapelle A, Gilliam TC, Lehesjoki AE (1999) The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8. Nat Genet 23(2):233–236
Salek RM, Colebrooke RE, Macintosh R, Lynch PJ, Sweatman BC, Emson PC, Griffin JL (2008) A metabolomic study of brain tissues from aged mice with low expression of the vesicular monoamine transporter 2 (VMAT2) gene. Neurochem Res 33(2):292–300
Salek RM, Xia J, Innes A, Sweatman BC, Adalbert R, Randle S, McGowan E, Emson PC, Griffin JL (2010) A metabolomic study of the CRND8 transgenic mouse model of Alzheimer’s disease. Neurochem Int 56(8):937–947
Sekhon SS, Maxwell DS (1974) Ultrastructural changes in neurons of the spinal anterior horn of ageing mice with particular reference to the accumulation of lipofuscin pigment. J Neurocytol 3(1):59–72
Trygg J, Wold S (2002) Orthogonal projections to latent structures (O-PLS). J Chemometr 16(3):119–128
Wheeler RB, Sharp JD, Schultz RA, Joslin JM, Williams RE, Mole SE (2002) The gene mutated in variant late-infantile neuronal ceroid lipofuscinosis (CLN6) and in nclf mutant mice encodes a novel predicted transmembrane protein. Am J Hum Genet 70(2):537–542
Wold S, Albano C, Dunn WJ, Edlund U, Esbensen K, Geladi P, Hellberg S, Johansson E, Lindberg W, Sjöström M (1984) Multivariate data analysis in chemistry. Chemometrics: mathematics and statistics in chemistry. D. Reidel Publishing Company, Holland
Acknowledgments
The authors would like to thank Dr. ChunHung Chan for help preparing the mice. This work was partially supported by Merck Sharp Dohme, NIH R21NS060185, NIH R21DK070288-01 and the Batten Disease Support and Research Association.
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Salek, R.M., Pears, M.R., Cooper, J.D. et al. A metabolomic comparison of mouse models of the Neuronal Ceroid Lipofuscinoses. J Biomol NMR 49, 175–184 (2011). https://doi.org/10.1007/s10858-011-9491-7
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DOI: https://doi.org/10.1007/s10858-011-9491-7