Adult neurogenesis is the life-long process of neural stem cell proliferation, differentiation into neurons, migration, and incorporation into the existing neuronal circuits. After decades of research, it is now widely accepted that mammals and birds retain the capacity to regenerate neurons even after their subadult ontogeny. Cerebrospinal fluid participates in the regulation of the neurogenic niches of the vertebrate brain through signaling pathways not fully elucidated. Proteomic studies of cerebrospinal fluid have the potential to allow the in-depth characterization of its molecular composition. Comparative studies help to delineate those pathways that are universally critical for the regulation of neurogenesis in adulthood. In this review, we performed literature-based data mining in studies using liquid chromatography-tandem mass spectroscopy that analyzed cerebrospinal fluid samples from healthy adult humans (Homo sapiens); mice (Mus musculus); sheep (Ovis aries); chickens (Gallus gallus); and two parrot species, the budgerigar (Melopsittacus undulatus) and cockatiel (Nymphicus hollandicus). We identified up to 911 proteins represented in cerebrospinal fluid, involved in various pathways regulating adult neurogenesis. However, only 196 proteins were common across humans, mice, and birds. Pathway components involved in nervous system development, cell migration, and axonal guidance were commonly evident in all species investigated so far. Extensive bioinformatic analysis revealed that the universally over-represented pathways involved L1 cell adhesion molecule protein interactions, cell-adhesion molecules, signals regulating extracellular matrix remodeling, regulation of insulin growth factor signaling, axonal guidance, programmed cell death, immune signaling, and post-translational modifications. Most of the reported proteins are part of extracellular vesicles enriched in cerebrospinal fluid. However, the information presently available is still highly fragmentary, and far more questions persist than are answered. Technological advances will allow cerebrospinal fluid comparative proteomic research to delve into the fundamental processes of adult neurogenesis and eventually translate this research into any regenerative interventions.

Department of Zoology Faculty of Science Charles University Prague Czech Republic

Zobrazit více v PubMed

Accogli A, Addour-Boudrahem N, Srour M. Neurogenesis, neuronal migration, and axon guidance. Handb Clin Neurol. 2020;173:25–42. PubMed

Aimone JB, Li Y, Lee SW, Clemenson GD, Deng W, Gage FH. Regulation and function of adult neurogenesis:from genes to cognition. Physiol Rev. 2014;94:991–1026. PubMed PMC

Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G. Gene Ontology:tool for the unification of biology. Nat Genet. 2000;25:25–29. PubMed PMC

Barnea A, Pravosudov V. Birds as a model to study adult neurogenesis:bridging evolutionary, comparative and neuroethological approaches. Eur J Neurosci. 2011;34:884–907. PubMed PMC

Bauer S, Patterson PH. Leukemia inhibitory factor promotes neural stem cell self-renewal in the adult brain. J Neurosci. 2006;26:12089–12099. PubMed PMC

Bereman MS, Beri J, Enders JR, Nash T. Machine learning reveals protein signatures in CSF and plasma fluids of clinical value for ALS. Sci Rep. 2018;8:16334. PubMed PMC

Červenka J, Tylečková J, KupcováSkalníková H, VodičkováKepková K, Poliakh I, Valeková I, Pfeiferová L, Kolář M, Vaškovičová M, Pánková T, Vodička P. Proteomic characterization of human neural stem cells and their secretome during in vitro differentiation. Front Cell Neurosci. 2021 doi:10.3389/fncel.2020.612560. PubMed PMC

Chen CPC, Preston JE, Zhou S, Fuller HR, Morgan DGA, Chen R. Proteomic analysis of age-related changes in ovine cerebrospinal fluid. Exp Gerontol. 2018;108:181–188. PubMed

Chiasserini D, van Weering JRT, Piersma SR, Pham TV, Malekzadeh A, Teunissen CE, de Wit H, Jiménez CR. Proteomic analysis of cerebrospinal fluid extracellular vesicles:a comprehensive dataset. J Proteomics. 2014;106:191–204. PubMed

Chintamen S, Imessadouene F, Kernie SG. Immune regulation of adult neurogenic niches in health and disease. Front Cell Neurosci. 2021 doi:10.3389/fncel.2020.571071. PubMed PMC

Dayon L, Cominetti O, Wojcik J, Galindo AN, Oikonomidi A, Henry H, Migliavacca E, Kussmann M, Bowman GL, Popp J. Proteomes of paired human cerebrospinal fluid and plasma:relation to blood-brain barrier permeability in older adults. J Proteome Res. 2019;18:1162–1174. PubMed

de Sonnaville SFAM, van Strien ME, Middeldorp J, Sluijs JA, van den Berge SA, Moeton M, Donega V, van Berkel A, Deering T, De Filippis L, Vescovi AL, Aronica E, Glass R, van de Berg WDJ, Swaab DF, Robe PA, Hol EM. The adult human subventricular zone:partial ependymal coverage and proliferative capacity of cerebrospinal fluid. Brain Communications. 2020 doi:10.1093/braincomms/fcaa150. PubMed PMC

Doetsch F, Scharff C. Challenges for brain repair:insights from adult neurogenesis in birds and mammals. BBE. 2001;58:306–322. PubMed

Fabregat A, Jupe S, Matthews L, Sidiropoulos K, Gillespie M, Garapati P, Haw R, Jassal B, Korninger F, May B, Milacic M, Roca CD, Rothfels K, Sevilla C, Shamovsky V, Shorser S, Varusai T, Viteri G, Weiser J, Wu G, et al. The reactome pathway knowledgebase. Nucl Acids Res. 2018;46:D649–655. PubMed PMC

Fame RM, Lehtinen MK. Emergence and developmental roles of the cerebrospinal fluid system. Dev Cell. 2020;52:261–275. PubMed

Fontán-Lozano Á, Morcuende S, Davis-López de Carrizosa MA, Benítez-Temiño B, Mejías R, Matarredona ER. To become or not to become tumorigenic:subventricular zone versus hippocampal neural stem cells. Front Oncol. 2020 doi:10.3389/fonc.2020.602217. PubMed PMC

Franzen AD, Lam TT, Williams KR, Nairn AC, Duman RS, Sathyanesan M, Kumar V, Carpenter LL, Newton SS. Cerebrospinal fluid proteome evaluation in major depressive disorder by mass spectrometry. BMC Psychiatry. 2020;20:481. PubMed PMC

Gato A, Alonso MI, Lamus F, Miyan J. Neurogenesis:a process ontogenically linked to brain cavities and their content, CSF. Semin Cell Dev Biol. 2020;102:21–27. PubMed

Geyer PE, Holdt LM, Teupser D, Mann M. Revisiting biomarker discovery by plasma proteomics. Mol Syst Biol. 2017;13:942. PubMed PMC

Hosp F, Gutiérrez-Ángel S, Schaefer MH, Cox J, Meissner F, Hipp MS, Hartl FU, Klein R, Dudanova I, Mann M. Spatiotemporal proteomic profiling of Huntington's disease inclusions reveals widespread loss of protein function. Cell Rep. 2017;21:2291–2303. PubMed PMC

Huang DW, Sherman BT, Zheng X, Yang J, Imamichi T, Stephens R, Lempicki RA. Extracting biological meaning from large gene lists with DAVID. Curr Protoc Bioinformatics Chapter. 2009;13:Unit–13.11. PubMed

Hulsen T, de Vlieg J, Alkema W. BioVenn –a web application for the comparison and visualization of biological lists using area-proportional Venn diagrams. BMC Genomics. 2008;9:488. PubMed PMC

Illes S. More than a drainage fluid:the role of CSF in signaling in the brain and other effects on brain tissue. Handb Clin Neurol. 2017;146:33–46. PubMed

Izsak J, Seth H, Theiss S, Hanse E, Illes S. Human cerebrospinal fluid promotes neuronal circuit maturation of human induced pluripotent stem cell-derived 3D neural aggregates. Stem Cell Reports. 2020;14:1044–1059. PubMed PMC

Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci U S A. 2002;99:11946–11950. PubMed PMC

Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, Higginbotham LA, Guajardo A, White B, Troncoso JC, Thambisetty M, Montine TJ, Lee EB, Trojanowski JQ, Beach TG, Reiman EM, Haroutunian V, Wang M, Schadt E, Zhang B, et al. Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020;26:769–780. PubMed PMC

Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. KEGG:new perspectives on genomes, pathways, diseases and drugs. Nucl Acids Res. 2017;45:D353–361. PubMed PMC

Kim SH, Turnbull J, Guimond S. Extracellular matrix and cell signalling:the dynamic cooperation of integrin, proteoglycan and growth factor receptor. J Endocrinol. 2011;209:139–151. PubMed

Kjell J, Fischer-Sternjak J, Thompson AJ, Friess C, Sticco MJ, Salinas F, Cox J, Martinelli DC, Ninkovic J, Franze K, Schiller HB, Götz M. Defining the adult neural stem cell niche proteome identifies key regulators of adult neurogenesis. Cell Stem Cell. 2020;26:277–293. PubMed PMC

Kokovay E, Wang Y, Kusek G, Wurster R, Lederman P, Lowry N, Shen Q, Temple S. VCAM1 is essential to maintain the structure of the SVZ niche and acts as an environmental sensor to regulate SVZ lineage progression. Cell Stem Cell. 2012;11:220–230. PubMed

Lehtinen Maria K, Zappaterra Mauro W, Chen X, Yang Yawei J, Hill AD, Lun M, Maynard T, Gonzalez D, Kim S, Ye P, D'Ercole AJ, Wong Eric T, LaMantia Anthony S, Walsh Christopher A. The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron. 2011;69:893–905. PubMed PMC

Lindsey BW, Tropepe V. A comparative framework for understanding the biological principles of adult neurogenesis. Prog Neurobiol. 2006;80:281–307. PubMed

Losurdo M, Grilli M. Extracellular vesicles, influential players of intercellular communication within adult neurogenic niches. Int J Mol Sci. 2020;21:8819. PubMed PMC

Lun MP, Monuki ES, Lehtinen MK. Development and functions of the choroid plexus–cerebrospinal fluid system. Nat Rev Neurosci. 2015;16:445–457. PubMed PMC

Macron C, Lavigne R, Núñez Galindo A, Affolter M, Pineau C, Dayon L. Exploration of human cerebrospinal fluid:a large proteome dataset revealed by trapped ion mobility time-of-flight mass spectrometry. Data Brief. 2020;31:105704. PubMed PMC

Mathieu P, Piantanida AP, Pitossi F. Chronic expression of transforming growth factor-beta enhances adult neurogenesis. Neuroimmunomodulation. 2010;17:200–201. PubMed

Nilsson C, Stahlberg F, Thomsen C, Henriksen O, Herning M, Owman C. Circadian variation in human cerebrospinal fluid production measured by magnetic resonance imaging. Am J Physiol. 1992;262:R20–24. PubMed

Obernier K, Alvarez-Buylla A. Neural stem cells:origin, heterogeneity and regulation in the adult mammalian brain. Development. 2019 doi:10.1242/dev.156059. PubMed PMC

Perez-Alcazar M, Culley G, Lyckenvik T, Mobarrez K, Bjorefeldt A, Wasling P, Seth H, Asztely F, Harrer A, Iglseder B, Aigner L, Hanse E, Illes S. Human cerebrospinal fluid promotes neuronal viability and activity of hippocampal neuronal circuits in vitro. Front Cell Neurosci. 2016;10:54. PubMed PMC

Pigoni M, Wanngren J, Kuhn PH, Munro KM, Gunnersen JM, Takeshima H, Feederle R, Voytyuk I, De Strooper B, Levasseur MD, Hrupka BJ, Müller SA, Lichtenthaler SF. Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons. Mol Neurodegener. 2016;11:67. PubMed PMC

R Core Team. R:A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2021. [Accessed October 13, 2021]. Available at:https://www.R-project.org/

Reiber H. Dynamics of brain-derived proteins in cerebrospinal fluid. Clinica Chimica Acta. 2001;310:173–186. PubMed

Rotunno MS, Lane M, Zhang W, Wolf P, Oliva P, Viel C, Wills AM, Alcalay RN, Scherzer CR, Shihabuddin LS, Zhang K, Sardi SP. Cerebrospinal fluid proteomics implicates the granin family in Parkinson's disease. Sci Rep. 2020;10:2479. PubMed PMC

Russell SA, Bashaw GJ. Axon guidance pathways and the control of gene expression. Dev Dyn. 2018;247:571–580. PubMed PMC

Salvador AF, de Lima KA, Kipnis J. Neuromodulation by the immune system:a focus on cytokines. Nat Rev Immunol. 2021;1:1–6. PubMed

Sathe G, Na CH, Renuse S, Madugundu AK, Albert M, Moghekar A, Pandey A. Quantitative proteomic profiling of cerebrospinal fluid to identify candidate biomarkers for Alzheimer's disease. Proteomics Clin Appl. 2018;13:e1800105. PubMed PMC

Schilde LM, Kösters S, Steinbach S, Schork K, Eisenacher M, Galozzi S, Turewicz M, Barkovits K, Mollenhauer B, Marcus K, May C. Protein variability in cerebrospinal fluid and its possible implications for neurological protein biomarker research. PLoS ONE. 2018;13:e0206478. PubMed PMC

Schmid RS, Maness PF. L1 and NCAM adhesion molecules as signaling co-receptors in neuronal migration and process outgrowth. Curr Opin Neurobiol. 2008;18:245–250. PubMed PMC

Schwarz N, Hedrich UBS, Schwarz H, P.a H, Dammeier N, Auffenberg E, Bedogni F, Honegger JB, Lerche H, Wuttke TV, Koch H. Human cerebrospinal fluid promotes long-term neuronal viability and network function in human neocortical organotypic brain slice cultures. Sci Rep. 2017;7:12249. PubMed PMC

Sierra A, Encinas JM, Deudero JJP, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, Tsirka SE, Maletic-Savatic M. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell. 2010;7:483–495. PubMed PMC

Silva-Vargas V, Maldonado-Soto Angel R, Mizrak D, Codega P, Doetsch F. Age-dependent niche signals from the choroid plexus regulate adult neural stem cells. Cell Stem Cell. 2016;19:643–652. PubMed

Sleat DE, Wiseman JA, El-Banna M, Zheng H, Zhao C, Soherwardy A, Moore DF, Lobel P. Analysis of brain and cerebrospinal fluid from mouse models of the three major forms of neuronal ceroid lipofuscinosis reveals changes in the lysosomal proteome. Mol Cell Proteomics. 2019;18:2244–2261. PubMed PMC

Sleat DE, Tannous A, Sohar I, Wiseman JA, Zheng H, Qian M, Zhao C, Xin W, Barone R, Sims KB, Moore DF, Lobel P. Proteomic analysis of brain and cerebrospinal fluid from the three major forms of neuronal ceroid lipofuscinosis reveals potential biomarkers. J Proteome Res. 2017;16:3787–3804. PubMed PMC

Spector R, Robert Snodgrass S, Johanson CE. A balanced view of the cerebrospinal fluid composition and functions:Focus on adult humans. Exp Neurol. 2015;273:57–68. PubMed

Swift J, Ivanovska IL, Buxboim A, Harada T, Dingal PCDP, Pinter J, Pajerowski JD, Spinler KR, Shin J-W, Tewari M, Rehfeldt F, Speicher DW, Discher DE. Nuclear Lamin-A Scales with Tissue Stiffness and Enhances Matrix-Directed Differentiation. Science. 2013;341:1240104. PubMed PMC

Thompson AG, Gray E, Thézénas ML, Charles PD, Evetts S, Hu MT, Talbot K, Fischer R, Kessler BM, Turner MR. Cerebrospinal fluid macrophage biomarkers in amyotrophic lateral sclerosis. Ann Neurol. 2018;83:258–268. PubMed

Ting L, Rad R, Gygi SP, Haas W. MS3 eliminates ratio distortion in isobaric multiplexed quantitative proteomics. Nat Methods. 2011;8:937–940. PubMed PMC

Tong CK, Han Y-G, Shah JK, Obernier K, Guinto CD, Alvarez-Buylla A. Primary cilia are required in a unique subpopulation of neural progenitors. Proc Natl Acad Sci U S A. 2014;111:12438–12443. PubMed PMC

Tu C, Rudnick PA, Martinez MY, Cheek KL, Stein SE, Slebos RJC, Liebler DC. Depletion of abundant plasma proteins and limitations of plasma proteomics. J Proteome Res. 2010;9:4982–4991. PubMed PMC

Tüshaus J, Müller SA, Kataka ES, Zaucha J, Sebastian Monasor L, Su M, Güner G, Jocher G, Tahirovic S, Frishman D, Simons M, Lichtenthaler SF. An optimized quantitative proteomics method establishes the cell type-resolved mouse brain secretome. EMBO J. 2020;39:e105693. PubMed PMC

Voukali E, Veetil NK, Němec P, Stopka P, Vinkler M. Comparison of plasma and cerebrospinal fluid proteomes identifies gene products guiding adult neurogenesis and neural differentiation in birds. Sci Rep. 2021;11:5312. PubMed PMC

Wang H, Dey KK, Chen PC, Li Y, Niu M, Cho JH, Wang X, Bai B, Jiao Y, Chepyala SR, Haroutunian V, Zhang B, Beach TG, Peng J. Integrated analysis of ultra-deep proteomes in cortex, cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer's disease. Mol Neurodegener. 2020;15:43. PubMed PMC

Wickham J, Corna A, Schwarz N, Uysal B, Layer N, Honegger JB, Wuttke TV, Koch H, Zeck G. Human cerebrospinal fluid induces neuronal excitability changes in resected human neocortical and hippocampal brain slices. Front Neurosci. 2020;14:283. PubMed PMC

You JS, Gelfanova V, Knierman MD, Witzmann FA, Wang M, Hale JE. The impact of blood contamination on the proteome of cerebrospinal fluid. Proteomics. 2005;5:290–296. PubMed

Yu G, Wang LG, Han Y, He QY. clusterProfiler:an R package for comparing biological themes among gene clusters. OMICS. 2012;16:284–287. PubMed PMC

Zappaterra MW, Lehtinen MK. The cerebrospinal fluid:regulator of neurogenesis, behavior, and beyond. Cell Mol Life Sci. 2012;69:2863–2878. PubMed PMC

Zhao M, Yang Y, Guo Z, Shao C, Sun H, Zhang Y, Sun Y, Liu Y, Song Y, Zhang L, Li Q, Liu J, Li M, Gao Y, Sun W. A comparative proteomics analysis of five body fluids:plasma, urine, cerebrospinal fluid, amniotic fluid, and saliva. Proteomics Clin Appl. 2018;12:e1800008. PubMed