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Proteomic Profiling in the Brain of CLN1 Disease Model Reveals Affected Functional Modules

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Abstract

Neuronal ceroid lipofuscinoses (NCL) are the most commonly inherited progressive encephalopathies of childhood. Pathologically, they are characterized by endolysosomal storage with different ultrastructural features and biochemical compositions. The molecular mechanisms causing progressive neurodegeneration and common molecular pathways linking expression of different NCL genes are largely unknown. We analyzed proteome alterations in the brains of a mouse model of human infantile CLN1 disease—palmitoyl-protein thioesterase 1 (Ppt1) gene knockout and its wild-type age-matched counterpart at different stages: pre-symptomatic, symptomatic and advanced. For this purpose, we utilized a combination of laser capture microdissection-based quantitative liquid chromatography tandem mass spectrometry (MS) and matrix-assisted laser desorption/ionization time-of-flight MS imaging to quantify/visualize the changes in protein expression in disease-affected brain thalamus and cerebral cortex tissue slices, respectively. Proteomic profiling of the pre-symptomatic stage thalamus revealed alterations mostly in metabolic processes and inhibition of various neuronal functions, i.e., neuritogenesis. Down-regulation in dynamics associated with growth of plasma projections and cellular protrusions was further corroborated by findings from RNA sequencing of CLN1 patients’ fibroblasts. Changes detected at the symptomatic stage included: mitochondrial functions, synaptic vesicle transport, myelin proteome and signaling cascades, such as RhoA signaling. Considerable dysregulation of processes related to mitochondrial cell death, RhoA/Huntington’s disease signaling and myelin sheath breakdown were observed at the advanced stage of the disease. The identified changes in protein levels were further substantiated by bioinformatics and network approaches, immunohistochemistry on brain tissues and literature knowledge, thus identifying various functional modules affected in the CLN1 childhood encephalopathy.

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Abbreviations

FDR:

False discovery rate

INCL/CLN1:

Classic infantile NCL

NCL:

Neuronal ceroid lipofuscinoses

LCM:

Laser capture microdissection

LC-MSE :

Liquid chromatography tandem mass spectrometry

LSDs:

Lysosomal storage disorders

MALDI-MSI:

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry imaging

PPT1:

Palmitoyl-protein thioesterase 1

Ppt1 −/− :

Ppt1 gene knockout

RNA-seq:

RNA sequence analysis

References

  • Aby, E., Gumps, K., Roth, A., Sigmon, S., Jenkins, S. E., Kim, J. J., et al. (2013). Mutations in palmitoyl-protein thioesterase 1 alter exocytosis and endocytosis at synapses in Drosophila larvae. Fly (Austin), 7(4), 267–279.

    Article  CAS  Google Scholar 

  • Ahtiainen, L., Kolikova, J., Mutka, A. L., Luiro, K., Gentile, M., Ikonen, E., et al. (2007). Palmitoyl protein thioesterase 1 (Ppt1)-deficient mouse neurons show alterations in cholesterol metabolism and calcium homeostasis prior to synaptic dysfunction. Neurobiology of Diseases, 28(1), 52–64.

    Article  CAS  Google Scholar 

  • Ahtiainen, L., Luiro, K., Kauppi, M., Tyynela, J., Kopra, O., & Jalanko, A. (2006). Palmitoyl protein thioesterase 1 (PPT1) deficiency causes endocytic defects connected to abnormal saposin processing. Experimental Cell Research, 312(9), 1540–1553.

    Article  CAS  PubMed  Google Scholar 

  • Ahtiainen, L., Van Diggelen, O. P., Jalanko, A., & Kopra, O. (2003). Palmitoyl protein thioesterase 1 is targeted to the axons in neurons. The Journal of Comparative Neurology, 455(3), 368–377.

    Article  CAS  PubMed  Google Scholar 

  • Anderson, G. W., Goebel, H. H., & Simonati, A. (2013). Human pathology in NCL. Biochimica et Biophysica Acta, 1832(11), 1807–1826.

    Article  CAS  PubMed  Google Scholar 

  • Ba, W., van der Raadt, J., & Nadif Kasri, N. (2013). Rho GTPase signaling at the synapse: Implications for intellectual disability. Experimental Cell Research, 319(15), 2368–2374.

    Article  CAS  PubMed  Google Scholar 

  • Bible, E., Gupta, P., Hofmann, S. L., & Cooper, J. D. (2004). Regional and cellular neuropathology in the palmitoyl protein thioesterase-1 null mutant mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiology of Diseases, 16(2), 346–359.

    Article  CAS  Google Scholar 

  • Blom, T., Schmiedt, M. L., Wong, A. M., Kyttala, A., Soronen, J., Jauhiainen, M., et al. (2013). Exacerbated neuronal ceroid lipofuscinosis phenotype in Cln1/5 double-knockout mice. Disease Models & Mechanisms., 6(2), 342–357.

    Article  CAS  Google Scholar 

  • Boustany, R. M. (2013). Lysosomal storage diseases—The horizon expands. Nature Reviews. Neurology, 9(10), 583–598.

    Article  CAS  PubMed  Google Scholar 

  • Braakman, R. B., Luider, T. M., Martens, J. W., Foekens, J. A., & Umar, A. (2011). Laser capture microdissection applications in breast cancer proteomics. Methods in Molecular Biology, 755, 143–154.

    Article  CAS  PubMed  Google Scholar 

  • Braakman, R. B., Tilanus-Linthorst, M. M., Liu, N. Q., Stingl, C., Dekker, L. J., Luider, T. M., et al. (2012). Optimized nLC-MS workflow for laser capture microdissected breast cancer tissue. Journal of Proteomics, 75(10), 2844–2854.

    Article  CAS  PubMed  Google Scholar 

  • Bronson, R. T., Donahue, L. R., Johnson, K. R., Tanner, A., Lane, P. W., & Faust, J. R. (1998). Neuronal ceroid lipofuscinosis (nclf), a new disorder of the mouse linked to chromosome 9. American Journal of Medical Genetics, 77(4), 289–297.

    Article  CAS  PubMed  Google Scholar 

  • Caldwell, R. L., & Caprioli, R. M. (2005). Tissue profiling by mass spectrometry: A review of methodology and applications. Molecular and Cellular Proteomics, 4(4), 394–401.

    Article  CAS  PubMed  Google Scholar 

  • Camp, L. A., & Hofmann, S. L. (1993). Purification and properties of a palmitoyl-protein thioesterase that cleaves palmitate from H-Ras. Journal of Biological Chemistry, 268(30), 22566–22574.

    CAS  PubMed  Google Scholar 

  • Cao, Y., Staropoli, J. F., Biswas, S., Espinola, J. A., MacDonald, M. E., Lee, J. M., et al. (2011). Distinct early molecular responses to mutations causing vLINCL and JNCL presage ATP synthase subunit C accumulation in cerebellar cells. PLoS ONE, 6(2), e17118.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chan, C. H., Want, E. J., Geraets, R., Weber, K., Hersrud, S., & Pearce, D. A. (2012) Biomarker Discovery in Batten Disease. In NCL2012, Roayl Holloway College, London, UK, 2012.

  • Cho, S., & Dawson, G. (2000). Palmitoyl protein thioesterase 1 protects against apoptosis mediated by Ras-Akt-caspase pathway in neuroblastoma cells. Journal of Neurochemistry, 74(4), 1478–1488.

    Article  CAS  PubMed  Google Scholar 

  • Chow, E., Mottahedeh, J., Prins, M., Ridder, W., Nusinowitz, S., & Bronstein, J. M. (2005). Disrupted compaction of CNS myelin in an OSP/Claudin-11 and PLP/DM20 double knockout mouse. Molecular and Cellular Neuroscience, 29(3), 405–413.

    Article  CAS  PubMed  Google Scholar 

  • Chrast, R., Saher, G., Nave, K. A., & Verheijen, M. H. (2011). Lipid metabolism in myelinating glial cells: Lessons from human inherited disorders and mouse models. Journal of Lipid Research, 52(3), 419–434.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chu-LaGraff, Q., Blanchette, C., O’Hern, P., & Denefrio, C. (2010). The batten disease palmitoyl protein thioesterase 1 gene regulates neural specification and axon connectivity during drosophila embryonic development. PLoS ONE, 5(12), e14402.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Conforti, L., Gilley, J., & Coleman, M. P. (2014). Wallerian degeneration: An emerging axon death pathway linking injury and disease. Nature Reviews Neuroscience, 15(6), 394–409.

    Article  CAS  PubMed  Google Scholar 

  • Das, A. M., Jolly, R. D., & Kohlschutter, A. (1999). Anomalies of mitochondrial ATP synthase regulation in four different types of neuronal ceroid lipofuscinosis. Molecular Genetics and Metabolism, 66(4), 349–355.

    Article  CAS  PubMed  Google Scholar 

  • Das, A. M., von Harlem, R., Feist, M., Lucke, T., & Kohlschutter, A. (2001). Altered levels of high-energy phosphate compounds in fibroblasts from different forms of neuronal ceroid lipofuscinoses: Further evidence for mitochondrial involvement. European Journal of Paediatric Neurology, 5(Suppl A), 143–146.

    Article  PubMed  Google Scholar 

  • D’Aversa, T. G., Eugenin, E. A., Lopez, L., & Berman, J. W. (2013). Myelin basic protein induces inflammatory mediators from primary human endothelial cells and blood-brain barrier disruption: Implications for the pathogenesis of multiple sclerosis. Neuropathology and Applied Neurobiology, 39(3), 270–283.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • de Monasterio-Schrader, P., Jahn, O., Tenzer, S., Wichert, S. P., Patzig, J., & Werner, H. B. (2012). Systematic approaches to central nervous system myelin. Cellular and Molecular Life Sciences, 69(17), 2879–2894.

    Article  CAS  PubMed  Google Scholar 

  • Devaux, J., & Gow, A. (2008). Tight junctions potentiate the insulative properties of small CNS myelinated axons. Journal of Cell Biology, 183(5), 909–921.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Eberlin, L. S., Liu, X., Ferreira, C. R., Santagata, S., Agar, N. Y., & Cooks, R. G. (2011). Desorption electrospray ionization then MALDI mass spectrometry imaging of lipid and protein distributions in single tissue sections. Analytical Chemistry, 83(22), 8366–8371.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Elshatory, Y., Brooks, A. I., Chattopadhyay, S., Curran, T. M., Gupta, P., Ramalingam, V., et al. (2003). Early changes in gene expression in two models of Batten disease. FEBS Letters, 538(1–3), 207–212.

    Article  CAS  PubMed  Google Scholar 

  • Faul, F., Erdfelder, E., Lang, A. G., & Buchner, A. (2007). G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods, 39(2), 175–191.

    Article  PubMed  Google Scholar 

  • Fiala, J. C., Spacek, J., & Harris, K. M. (2002). Dendritic spine pathology: Cause or consequence of neurological disorders? Brain Research. Brain Research Reviews, 39(1), 29–54.

    Article  PubMed  Google Scholar 

  • Findley, M. K., & Koval, M. (2009). Regulation and roles for claudin-family tight junction proteins. IUBMB Life, 61(4), 431–437.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gerdts, J., Brace, E. J., Sasaki, Y., DiAntonio, A., & Milbrandt, J. (2015). SARM1 activation triggers axon degeneration locally via NAD(+) destruction. Science, 348(6233), 453–457.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Goswami, R., Ahmed, M., Kilkus, J., Han, T., Dawson, S. A., & Dawson, G. (2005). Differential regulation of ceramide in lipid-rich microdomains (rafts): Antagonistic role of palmitoyl:protein thioesterase and neutral sphingomyelinase 2. Journal of Neuroscience Research, 81(2), 208–217.

    Article  CAS  PubMed  Google Scholar 

  • Groh, J., Kuhl, T. G., Ip, C. W., Nelvagal, H. R., Sri, S., Duckett, S., et al. (2013). Immune cells perturb axons and impair neuronal survival in a mouse model of infantile neuronal ceroid lipofuscinosis. Brain, 136(Pt 4), 1083–1101.

    Article  PubMed  Google Scholar 

  • Gupta, P., Soyombo, A. A., Atashband, A., Wisniewski, K. E., Shelton, J. M., Richardson, J. A., et al. (2001). Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. Proceedings of the National Academy of Sciences of the United States of America, 98(24), 13566–13571.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Haltia, M. (2006). The neuronal ceroid-lipofuscinoses: from past to present. Biochimica et Biophysica Acta, 1762(10), 850–856.

    Article  CAS  PubMed  Google Scholar 

  • Haltia, M., Rapola, J., & Santavuori, P. (1973a). Infantile type of so-called neuronal ceroid-lipofuscinosis. Histological and electron microscopic studies. Acta Neuropathologica, 26(2), 157–170.

    Article  CAS  PubMed  Google Scholar 

  • Haltia, M., Rapola, J., Santavuori, P., & Keranen, A. (1973b). Infantile type of so-called neuronal ceroid-lipofuscinosis. 2. Morphological and biochemical studies. Journal of the Neurological Sciences, 18(3), 269–285.

    Article  CAS  PubMed  Google Scholar 

  • Heinonen, O., Kyttala, A., Lehmus, E., Paunio, T., Peltonen, L., & Jalanko, A. (2000). Expression of palmitoyl protein thioesterase in neurons. Molecular Genetics and Metabolism, 69(2), 123–129.

    Article  CAS  PubMed  Google Scholar 

  • Hofmann, S. L., Das, A. K., Yi, W., Lu, J. Y., & Wisniewski, K. E. (1999). Genotype-phenotype correlations in neuronal ceroid lipofuscinosis due to palmitoyl-protein thioesterase deficiency. Molecular Genetics and Metabolism, 66(4), 234–239.

    Article  CAS  PubMed  Google Scholar 

  • Ikem, A. (2010). Measurement of volatile organic compounds in bottled and tap waters by purge and trap GC–MS: Are drinking water types different? Journal of Food Composition and Analysis, 23(1), 70–77.

    Article  CAS  Google Scholar 

  • Isosomppi, J., Heinonen, O., Hiltunen, J. O., Greene, N. D., Vesa, J., Uusitalo, A., et al. (1999). Developmental expression of palmitoyl protein thioesterase in normal mice. Brain Research. Developmental Brain Research, 118(1–2), 1–11.

    Article  CAS  PubMed  Google Scholar 

  • Jahn, O., Tenzer, S., & Werner, H. B. (2009). Myelin proteomics: Molecular anatomy of an insulating sheath. Molecular Neurobiology, 40(1), 55–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jalanko, A., Tyynela, J., & Peltonen, L. (2006). From genes to systems: New global strategies for the characterization of NCL biology. Biochimica et Biophysica Acta, 1762(10), 934–944.

    Article  CAS  PubMed  Google Scholar 

  • Jalanko, A., Vesa, J., Manninen, T., von Schantz, C., Minye, H., Fabritius, A. L., et al. (2005). Mice with Ppt1Deltaex4 mutation replicate the INCL phenotype and show an inflammation-associated loss of interneurons. Neurobiology of Diseases, 18(1), 226–241.

    Article  CAS  Google Scholar 

  • 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. Journal of Neurochemistry, 84(5), 1051–1065.

    Article  CAS  PubMed  Google Scholar 

  • Kamate, M., & Hattiholi, V. (2012). Novel neuroimaging finding in palmitoyl protein thioesterase-1-related neuronal ceroid lipofuscinosis. Pediatric Neurology, 46(5), 325–328.

    Article  PubMed  Google Scholar 

  • Karlsson, O., Bergquist, J., & Andersson, M. (2014). Quality measures of imaging mass spectrometry aids in revealing long-term striatal protein changes induced by neonatal exposure to the cyanobacterial toxin beta-N-methylamino-l-alanine (BMAA). Molecular and Cellular Proteomics, 13(1), 93–104.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kielar, C., Maddox, L., Bible, E., Pontikis, C. C., Macauley, S. L., Griffey, M. A., et al. (2007). Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiology of Diseases, 25(1), 150–162.

    Article  CAS  Google Scholar 

  • Kielar, C., Wishart, T. M., Palmer, A., Dihanich, S., Wong, A. M., Macauley, S. L., et al. (2009). Molecular correlates of axonal and synaptic pathology in mouse models of batten disease. Human Molecular Genetics, 18(21), 4066–4080.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kim, S. J., Zhang, Z., Lee, Y. C., & Mukherjee, A. B. (2006). Palmitoyl-protein thioesterase-1 deficiency leads to the activation of caspase-9 and contributes to rapid neurodegeneration in INCL. Human Molecular Genetics, 15(10), 1580–1586.

    Article  CAS  PubMed  Google Scholar 

  • Kim, S. J., Zhang, Z., Sarkar, C., Tsai, P. C., Lee, Y. C., Dye, L., et al. (2008). Palmitoyl protein thioesterase-1 deficiency impairs synaptic vesicle recycling at nerve terminals, contributing to neuropathology in humans and mice. The Journal of Clinical Investigation, 118(9), 3075–3086.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Koch, S., Scifo, E., Rokka, A., Trippner, P., Lindfors, M., Korhonen, R., et al. (2013). Cathepsin D deficiency induces cytoskeletal changes and affects cell migration pathways in the brain. Neurobiology of Diseases, 50, 107–119.

    Article  CAS  Google Scholar 

  • Kopra, O., Vesa, J., von Schantz, C., Manninen, T., Minye, H., Fabritius, A. L., et al. (2004). A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging. Human Molecular Genetics, 13(23), 2893–2906.

    Article  CAS  PubMed  Google Scholar 

  • Kousi, M., Lehesjoki, A. E., & Mole, S. E. (2012). Update on the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Human Mutation, 33(1), 42–63.

    Article  CAS  PubMed  Google Scholar 

  • Kuronen, M., Hermansson, M., Manninen, O., Zech, I., Talvitie, M., Laitinen, T., et al. (2012). Galactolipid deficiency in the early pathogenesis of neuronal ceroid lipofuscinosis model Cln8mnd: Implications to delayed myelination and oligodendrocyte maturation. Neuropathology and Applied Neurobiology, 38(5), 471–486.

    Article  CAS  PubMed  Google Scholar 

  • Lalowski, M., Magni, F., Mainini, V., Monogioudi, E., Gotsopoulos, A., Soliymani, R., et al. (2013). Imaging mass spectrometry: A new tool for kidney disease investigations. Nephrology, Dialysis, Transplantation, 28(7), 1648–1656.

    Article  PubMed  Google Scholar 

  • Lee, D. W., Banquy, X., Kristiansen, K., Kaufman, Y., Boggs, J. M., & Israelachvili, J. N. (2014). Lipid domains control myelin basic protein adsorption and membrane interactions between model myelin lipid bilayers. Proceedings of the National Academy of Sciences of the United States of America, 111(8), E768–E775.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lehrer, S., Roboz, J., Ding, H., Zhao, S., Diamond, E. J., Holland, J. F., et al. (2003). Putative protein markers in the sera of men with prostatic neoplasms. BJU International, 92(3), 223–225.

    Article  CAS  PubMed  Google Scholar 

  • Lehtovirta, M., Kyttala, A., Eskelinen, E. L., Hess, M., Heinonen, O., & Jalanko, A. (2001). Palmitoyl protein thioesterase (PPT) localizes into synaptosomes and synaptic vesicles in neurons: implications for infantile neuronal ceroid lipofuscinosis (INCL). Human Molecular Genetics, 10(1), 69–75.

    Article  CAS  PubMed  Google Scholar 

  • Leverenz, J. B., Umar, I., Wang, Q., Montine, T. J., McMillan, P. J., Tsuang, D. W., et al. (2007). Proteomic identification of novel proteins in cortical Lewy bodies. Brain Pathology, 17(2), 139–145.

    Article  CAS  PubMed  Google Scholar 

  • Liu, N. Q., Braakman, R. B., Stingl, C., Luider, T. M., Martens, J. W., Foekens, J. A., et al. (2012). Proteomics pipeline for biomarker discovery of laser capture microdissected breast cancer tissue. J Mammary Gland Biol Neoplasia, 17(2), 155–164.

    Article  PubMed Central  PubMed  Google Scholar 

  • Luiro, K., Kopra, O., Blom, T., Gentile, M., Mitchison, H. M., Hovatta, I., et al. (2006). Batten disease (JNCL) is linked to disturbances in mitochondrial, cytoskeletal, and synaptic compartments. Journal of Neuroscience Research, 84(5), 1124–1138.

    Article  CAS  PubMed  Google Scholar 

  • Lyly, A., Marjavaara, S. K., Kyttala, A., Uusi-Rauva, K., Luiro, K., Kopra, O., et al. (2008). Deficiency of the INCL protein Ppt1 results in changes in ectopic F1-ATP synthase and altered cholesterol metabolism. Human Molecular Genetics, 17(10), 1406–1417.

    Article  CAS  PubMed  Google Scholar 

  • Lyly, A., von Schantz, C., Heine, C., Schmiedt, M. L., Sipila, T., Jalanko, A., et al. (2009). Novel interactions of CLN5 support molecular networking between Neuronal Ceroid Lipofuscinosis proteins. BMC Cell Biology, 10, 83.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Macauley, S. L., Pekny, M., & Sands, M. S. (2011). The role of attenuated astrocyte activation in infantile neuronal ceroid lipofuscinosis. Journal of Neuroscience, 31(43), 15575–15585.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Maier, S. K., Hahne, H., Gholami, A. M., Balluff, B., Meding, S., Schoene, C., et al. (2013). Comprehensive identification of proteins from MALDI imaging. Molecular and Cellular Proteomics, 12(10), 2901–2910.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mainini, V., Lalowski, M., Gotsopoulos, A., Bitsika, V., Baumann, M., & Magni, F. (2015). MALDI-imaging mass spectrometry on tissues. Methods in Molecular Biology, 1243, 139–164.

    Article  PubMed  Google Scholar 

  • Margolis, R. L., & Ross, C. A. (2003). Diagnosis of Huntington disease. Clinical Chemistry, 49(10), 1726–1732.

    Article  CAS  PubMed  Google Scholar 

  • McCarthy, D. P., Richards, M. H., & Miller, S. D. (2012). Mouse models of multiple sclerosis: Experimental autoimmune encephalomyelitis and Theiler’s virus-induced demyelinating disease. Methods in Molecular Biology, 900, 381–401.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • McDonnell, L. A., Walch, A., Stoeckli, M., & Corthals, G. L. (2014). MSiMass list: A public database of identifications for protein MALDI MS imaging. Journal of Proteome Research, 13(2), 1138–1142.

    Article  CAS  PubMed  Google Scholar 

  • Milde, S., Fox, A. N., Freeman, M. R., & Coleman, M. P. (2013a). Deletions within its subcellular targeting domain enhance the axon protective capacity of Nmnat2 in vivo. Scientific Reports, 3, 2567.

    Article  PubMed Central  PubMed  Google Scholar 

  • Milde, S., Gilley, J., & Coleman, M. P. (2013b). Subcellular localization determines the stability and axon protective capacity of axon survival factor Nmnat2. PLoS Biology, 11(4), e1001539.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Miller, J. N., Kovacs, A. D., & Pearce, D. A. (2015). The novel Cln1R151X mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy. Human Molecular Genetics, 24(1), 185–196.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Miravalle, L., Calero, M., Takao, M., Roher, A. E., Ghetti, B., & Vidal, R. (2005). Amino-terminally truncated Abeta peptide species are the main component of cotton wool plaques. Biochemistry, 44(32), 10810–10821.

    Article  CAS  PubMed  Google Scholar 

  • Morgan, J. P., Magee, H., Wong, A., Nelson, T., Koch, B., Cooper, J. D., et al. (2013). A murine model of variant late infantile ceroid lipofuscinosis recapitulates behavioral and pathological phenotypes of human disease. PLoS ONE, 8(11), e78694.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mutka, A. L., Haapanen, A., Kakela, R., Lindfors, M., Wright, A. K., Inkinen, T., et al. (2010). Murine cathepsin D deficiency is associated with dysmyelination/myelin disruption and accumulation of cholesteryl esters in the brain. Journal of Neurochemistry, 112(1), 193–203.

    Article  CAS  PubMed  Google Scholar 

  • Nave, K. A. (2010). Myelination and support of axonal integrity by glia. Nature, 468(7321), 244–252.

    Article  CAS  PubMed  Google Scholar 

  • Nave, K. A., & Trapp, B. D. (2008). Axon-glial signaling and the glial support of axon function. Annual Review of Neuroscience, 31, 535–561.

    Article  CAS  PubMed  Google Scholar 

  • Newey, S. E., Velamoor, V., Govek, E. E., & Van Aelst, L. (2005). Rho GTPases, dendritic structure, and mental retardation. Journal of Neurobiology, 64(1), 58–74.

    Article  CAS  PubMed  Google Scholar 

  • Ng, K. P., Gugiu, B., Renganathan, K., Davies, M. W., Gu, X., Crabb, J. S., et al. (2008). Retinal pigment epithelium lipofuscin proteomics. Molecular and Cellular Proteomics, 7(7), 1397–1405.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ohno, N., Kidd, G. J., Mahad, D., Kiryu-Seo, S., Avishai, A., Komuro, H., et al. (2011). Myelination and axonal electrical activity modulate the distribution and motility of mitochondria at CNS nodes of Ranvier. Journal of Neuroscience, 31(20), 7249–7258.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ottis, P., Koppe, K., Onisko, B., Dynin, I., Arzberger, T., Kretzschmar, H., et al. (2012). Human and rat brain lipofuscin proteome. Proteomics, 12(15–16), 2445–2454.

    Article  CAS  PubMed  Google Scholar 

  • Palmer, D. N., Barry, L. A., Tyynela, J., & Cooper, J. D. (2013). NCL disease mechanisms. Biochimica et Biophysica Acta, 1832(11), 1882–1893.

    Article  CAS  PubMed  Google Scholar 

  • Patzig, J., Jahn, O., Tenzer, S., Wichert, S. P., de Monasterio-Schrader, P., Rosfa, S., et al. (2011). Quantitative and integrative proteome analysis of peripheral nerve myelin identifies novel myelin proteins and candidate neuropathy loci. Journal of Neuroscience, 31(45), 16369–16386.

    Article  CAS  PubMed  Google Scholar 

  • Pezzini, F., Gismondi, F., Tessa, A., Tonin, P., Carrozzo, R., Mole, S. E., et al. (2011). Involvement of the mitochondrial compartment in human NCL fibroblasts. Biochemical and Biophysical Research Communications, 416(1–2), 159–164.

    Article  CAS  PubMed  Google Scholar 

  • Philipson, O., Lord, A., Lalowski, M., Soliymani, R., Baumann, M., Thyberg, J., et al. (2012). The Arctic amyloid-beta precursor protein (AbetaPP) mutation results in distinct plaques and accumulation of N- and C-truncated Abeta. Neurobiol Aging, 33(5), 1010e1–1010e13.

  • Saab, A. S., Tzvetanova, I. D., & Nave, K. A. (2013). The role of myelin and oligodendrocytes in axonal energy metabolism. Current Opinion in Neurobiology, 23(6), 1065–1072.

    Article  CAS  PubMed  Google Scholar 

  • Santorelli, F. M., Bertini, E., Petruzzella, V., Di Capua, M., Calvieri, S., Gasparini, P., et al. (1998). A novel insertion mutation (A169i) in the CLN1 gene is associated with infantile neuronal ceroid lipofuscinosis in an Italian patient. Biochemical and Biophysical Research Communications, 245(2), 519–522.

    Article  CAS  PubMed  Google Scholar 

  • Schaefer, M. H., Fontaine, J. F., Vinayagam, A., Porras, P., Wanker, E. E., & Andrade-Navarro, M. A. (2012). HIPPIE: Integrating protein interaction networks with experiment based quality scores. PLoS ONE, 7(2), e31826.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schmiedt, M. L., Blom, T., Kopra, O., Wong, A., von Schantz-Fant, C., Ikonen, E., et al. (2012). Cln5-deficiency in mice leads to microglial activation, defective myelination and changes in lipid metabolism. Neurobiology of Diseases, 46(1), 19–29.

    Article  CAS  Google Scholar 

  • Schon, E. A., & Manfredi, G. (2003). Neuronal degeneration and mitochondrial dysfunction. The Journal of Clinical Investigation, 111(3), 303–312.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Scifo, E., Szwajda, A., Debski, J., Uusi-Rauva, K., Kesti, T., Dadlez, M., et al. (2013). Drafting the CLN3 protein interactome in SH-SY5Y human neuroblastoma cells: A label-free quantitative proteomics approach. Journal of Proteome Research, 12(5), 2101–2115.

    Article  CAS  PubMed  Google Scholar 

  • Scifo, E., Szwajda, A., Soliymani, R., Pezzini, F., Bianchi, M., Dapkunas, A., et al. (2015a). Quantitative analysis of PPT1 interactome in human neuroblastoma cells. Data in Brief, 4, 207–216.

    Article  PubMed Central  PubMed  Google Scholar 

  • Scifo, E., Szwajda, A., Soliymani, R., Pezzini, F., Bianchi, M., Dapkunas, A., et al. (2015b). Proteomic analysis of the palmitoyl protein thioesterase 1 interactome in SH-SY5Y human neuroblastoma cells. J Proteomics, 123, 42–53.

    Article  CAS  PubMed  Google Scholar 

  • Simonati, A., Tessa, A., Bernardina, B. D., Biancheri, R., Veneselli, E., Tozzi, G., et al. (2009). Variant late infantile neuronal ceroid lipofuscinosis because of CLN1 mutations. Pediatric Neurology, 40(4), 271–276.

    Article  PubMed  Google Scholar 

  • Stingl, C., van Vilsteren, F. G., Guzel, C., Ten Kate, F. J., Visser, M., Krishnadath, K. K., et al. (2011). Reproducibility of protein identification of selected cell types in Barrett’s esophagus analyzed by combining laser-capture microdissection and mass spectrometry. Journal of Proteome Research, 10(1), 288–298.

    Article  CAS  PubMed  Google Scholar 

  • Suopanki, J., Tyynela, J., Baumann, M., & Haltia, M. (1999a). The expression of palmitoyl-protein thioesterase is developmentally regulated in neural tissues but not in nonneural tissues. Molecular Genetics and Metabolism, 66(4), 290–293.

    Article  CAS  PubMed  Google Scholar 

  • Suopanki, J., Tyynela, J., Baumann, M., & Haltia, M. (1999b). Palmitoyl-protein thioesterase, an enzyme implicated in neurodegeneration, is localized in neurons and is developmentally regulated in rat brain. Neuroscience Letters, 265(1), 53–56.

    Article  CAS  PubMed  Google Scholar 

  • Tardy, C., Sabourdy, F., Garcia, V., Jalanko, A., Therville, N., Levade, T., et al. (2009). Palmitoyl protein thioesterase 1 modulates tumor necrosis factor alpha-induced apoptosis. Biochimica et Biophysica Acta, 1793(7), 1250–1258.

    Article  CAS  PubMed  Google Scholar 

  • Taylor, C. M., Marta, C. B., Claycomb, R. J., Han, D. K., Rasband, M. N., Coetzee, T., et al. (2004). Proteomic mapping provides powerful insights into functional myelin biology. Proceedings of the National Academy of Sciences of the United States of America, 101(13), 4643–4648.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Trapnell, C., Roberts, A., Goff, L., Pertea, G., Kim, D., Kelley, D. R., et al. (2012). Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nature Protocols, 7(3), 562–578.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Umar, A., Dalebout, J. C., Timmermans, A. M., Foekens, J. A., & Luider, T. M. (2005). Method optimisation for peptide profiling of microdissected breast carcinoma tissue by matrix-assisted laser desorption/ionisation-time of flight and matrix-assisted laser desorption/ionisation-time of flight/time of flight-mass spectrometry. Proteomics, 5(10), 2680–2688.

    Article  CAS  PubMed  Google Scholar 

  • van Beveren, N. J., Krab, L. C., Swagemakers, S., Buitendijk, G. H., Boot, E., van der Spek, P., et al. (2012). Functional gene-expression analysis shows involvement of schizophrenia-relevant pathways in patients with 22q11 deletion syndrome. PLoS ONE, 7(3), e33473.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • van der Knaap, M. S., & Vaap, J. (2005). Magnetic resonance of myelination and myelin disorders (3rd ed.). Berlin: Springer.

    Book  Google Scholar 

  • van Spronsen, M., & Hoogenraad, C. C. (2010). Synapse pathology in psychiatric and neurologic disease. Current Neurology and Neuroscience Reports, 10(3), 207–214.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Vanhanen, S. L., Puranen, J., Autti, T., Raininko, R., Liewendahl, K., Nikkinen, P., et al. (2004). Neuroradiological findings (MRS, MRI, SPECT) in infantile neuronal ceroid-lipofuscinosis (infantile CLN1) at different stages of the disease. Neuropediatrics, 35(1), 27–35.

    Article  PubMed  Google Scholar 

  • Vanrobaeys, F., Van Coster, R., Dhondt, G., Devreese, B., & Van Beeumen, J. (2005). Profiling of myelin proteins by 2D-gel electrophoresis and multidimensional liquid chromatography coupled to MALDI TOF-TOF mass spectrometry. Journal of Proteome Research, 4(6), 2283–2293.

    Article  CAS  PubMed  Google Scholar 

  • Vesa, J., Chin, M. H., Oelgeschlager, K., Isosomppi, J., DellAngelica, E. C., Jalanko, A., et al. (2002). Neuronal ceroid lipofuscinoses are connected at molecular level: interaction of CLN5 protein with CLN2 and CLN3. Molecular Biology of the Cell, 13(7), 2410–2420.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Vesa, J., Hellsten, E., Verkruyse, L. A., Camp, L. A., Rapola, J., Santavuori, P., et al. (1995). Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Nature, 376(6541), 584–587.

    Article  CAS  PubMed  Google Scholar 

  • Virmani, T., Gupta, P., Liu, X., Kavalali, E. T., & Hofmann, S. L. (2005). Progressively reduced synaptic vesicle pool size in cultured neurons derived from neuronal ceroid lipofuscinosis-1 knockout mice. Neurobiology of Diseases, 20(2), 314–323.

    Article  CAS  Google Scholar 

  • von Schantz, C., Saharinen, J., Kopra, O., Cooper, J. D., Gentile, M., Hovatta, I., et al. (2008). Brain gene expression profiles of Cln1 and Cln5 deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases. BMC Genomics, 9, 146.

    Article  CAS  Google Scholar 

  • Wang, P., Ju, W., Wu, D., Wang, L., Yan, M., Zou, J., et al. (2011). A two-dimensional protein fragmentation-proteomic study of neuronal ceroid lipofuscinoses: Identification and characterization of differentially expressed proteins. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences, 879(5–6), 304–316.

    Article  CAS  PubMed  Google Scholar 

  • Warburton, S., Southwick, K., Hardman, R. M., Secrest, A. M., Grow, R. K., Xin, H., et al. (2005). Examining the proteins of functional retinal lipofuscin using proteomic analysis as a guide for understanding its origin. Molecular Visions, 11, 1122–1134.

    CAS  Google Scholar 

  • Warde-Farley, D., Donaldson, S. L., Comes, O., Zuberi, K., Badrawi, R., & Chao, P., et al. (2010). The GeneMANIA prediction server: Biological network integration for gene prioritization and predicting gene function. Nucleic Acids Research, 38(Web Server issue), W214–W220.

  • Wei, H., Zhang, Z., Saha, A., Peng, S., Chandra, G., Quezado, Z., et al. (2011). Disruption of adaptive energy metabolism and elevated ribosomal p-S6K1 levels contribute to INCL pathogenesis: Partial rescue by resveratrol. Human Molecular Genetics, 20(6), 1111–1121.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wirsching, H. G., Krishnan, S., Florea, A. M., Frei, K., Krayenbuhl, N., Hasenbach, K., et al. (2014). Thymosin beta 4 gene silencing decreases stemness and invasiveness in glioblastoma. Brain, 137(Pt 2), 433–448.

    Article  PubMed  Google Scholar 

  • Wisztorski, M., Croix, D., Macagno, E., Fournier, I., & Salzet, M. (2008). Molecular MALDI imaging: An emerging technology for neuroscience studies. Developmental Neurobiology, 68(6), 845–858.

    Article  CAS  PubMed  Google Scholar 

  • Xu, B. J. (2010). Combining laser capture microdissection and proteomics: Methodologies and clinical applications. Proteomics. Clinical Applications, 4(2), 116–123.

    Article  CAS  PubMed  Google Scholar 

  • Yang, J., Gu, P., Menges, S., & Klassen, H. (2012). Quantitative changes in gene transcription during induction of differentiation in porcine neural progenitor cells. Molecular Visions, 18, 1484–1504.

    CAS  Google Scholar 

  • Zhang, Y. Q., Henderson, M. X., Colangelo, C. M., Ginsberg, S. D., Bruce, C., Wu, T., et al. (2012). Identification of CSPalpha clients reveals a role in dynamin 1 regulation. Neuron, 74(1), 136–150.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang, Z., Lee, Y. C., Kim, S. J., Choi, M. S., Tsai, P. C., Xu, Y., et al. (2006). Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL. Human Molecular Genetics, 15(2), 337–346.

    Article  CAS  PubMed  Google Scholar 

  • Zimmerman, T. A., Monroe, E. B., Tucker, K. R., Rubakhin, S. S., & Sweedler, J. V. (2008). Chapter 13: imaging of cells and tissues with mass spectrometry: Adding chemical information to imaging. Methods in Cell Biology, 89, 361–390.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zuberi, K., Franz, M., Rodriguez, H., Montojo, J., Lopes, C. T., Bader, G. D., et al. (2013). GeneMANIA prediction server 2013 update. Nucleic Acids Research, 41, W115–W122.

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The authors wish to thank the colleagues of the Functional Genomic Centre of Verona University, Verona, Italy, for performing RNA-seq analysis. Patients’ fibroblasts were referred to AS within the collaborative framework of CLNet, the Italian Network of CLN investigators. The authors also thank Teija Inkinen and Suvi Saarnio for excellent technical assistance, Essi Kaiharju for helping with mice preparations and Adjunct Professor Ove Eriksson for valuable comments on the manuscript. Professor Anna-Elina Lehesjoki is thanked for management of the DEM-CHILD project and overall support.

Funding

This study was funded by the European Community’s Seventh Framework Program (FP7/2007–2013) under Grant Agreement No. 281234; DEM-CHILD and partially by the Academy of Finland (#128600) to ML. AG was funded by the University of Helsinki and Aalto University collaborative grant.

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Author notes

  1. Evanthia Monogioudi

    Present address: Joint Research Centre, Directorate D–Institute for Reference Materials and Measurements, Standards for Innovation and Sustainable Development, Geel, Belgium

  2. Enzo Scifo

    Present address: Campbell Family Mental Health Research Institute, CAMH, University of Toronto, Toronto, Canada

Authors and Affiliations

  1. Medicum, Biochemistry/Developmental Biology, Meilahti Clinical Proteomics Core Facility, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), Room C214a, 00014, Helsinki, Finland

    Saara Tikka, Rabah Soliymani, Enzo Scifo, Jaana Tyynelä, Marc Baumann & Maciej Lalowski

  2. Folkhälsan Institute of Genetics, 00014, Helsinki, Finland

    Saara Tikka, Evanthia Monogioudi, Kristiina Uusi-Rauva & Maciej Lalowski

  3. Brain and Mind Laboratory, Department of Biomedical Engineering and Computational Science (BECS), Aalto University School of Science, 02150, Espoo, Finland

    Athanasios Gotsopoulos

  4. Department of Neurological and Movement Sciences, University of Verona, 37134, Verona, Italy

    Francesco Pezzini & Alessandro Simonati

  5. Institute for Molecular Medicine (FIMM), University of Helsinki, 00014, Helsinki, Finland

    Anu Jalanko

  6. Genomics and Biomarkers, National Institute for Health and Welfare (THL), P.O. Box 30, 00271, Helsinki, Finland

    Kristiina Uusi-Rauva & Anu Jalanko

  7. Doctoral Program Brain & Mind, University of Helsinki, Helsinki, Finland

    Enzo Scifo

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Saara Tikka and Evanthia Monogioudi have contributed equally to this work.

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Tikka, S., Monogioudi, E., Gotsopoulos, A. et al. Proteomic Profiling in the Brain of CLN1 Disease Model Reveals Affected Functional Modules. Neuromol Med 18, 109–133 (2016). https://doi.org/10.1007/s12017-015-8382-6

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