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Reaching Out to Send a Message: Proteins Associated with Neurite Outgrowth and Neurotransmission are Altered with Age in the Long-Lived Naked Mole-Rat

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Abstract

Aging is the greatest risk factor for developing neurodegenerative diseases, which are associated with diminished neurotransmission as well as neuronal structure and function. However, several traits seemingly evolved to avert or delay age-related deterioration in the brain of the longest-lived rodent, the naked mole-rat (NMR). The NMR remarkably also exhibits negligible senescence, maintaining an extended healthspan for ~75 % of its life span. Using a proteomic approach, statistically significant changes with age in expression and/or phosphorylation levels of proteins associated with neurite outgrowth and neurotransmission were identified in the brain of the NMR and include: cofilin-1; collapsin response mediator protein 2; actin depolymerizing factor; spectrin alpha chain; septin-7; syntaxin-binding protein 1; synapsin-2 isoform IIB; and dynamin 1. We hypothesize that such changes may contribute to the extended lifespan and healthspan of the NMR.

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References

  1. Andziak B, O’Connor TP, Qi W, DeWaal EM, Pierce A, Chaudhuri AR, Van Remmen H, Buffenstein R (2006) High oxidative damage levels in the longest-living rodent, the naked mole-rat. Aging Cell 5(6):463–471

    Article  CAS  PubMed  Google Scholar 

  2. Baines AJ (2009) Evolution of spectrin function in cytoskeletal and membrane networks. Biochem Soc Trans 37(Pt 4):796–803

    Article  CAS  PubMed  Google Scholar 

  3. Barclay JW, Craig TJ, Fisher RJ, Ciufo LF, Evans GJ, Morgan A, Burgoyne RD (2003) Phosphorylation of Munc18 by protein kinase C regulates the kinetics of exocytosis. J Biol Chem 278(12):10538–10545

    Article  CAS  PubMed  Google Scholar 

  4. Barral Y, Mermall V, Mooseker MS, Snyder M (2000) Compartmentalization of the cell cortex by septins is required for maintenance of cell polarity in yeast. Mol Cell 5(5):841–851

    Article  CAS  PubMed  Google Scholar 

  5. Brittain JM, Piekarz AD, Wang Y, Kondo T, Cummins TR, Khanna R (2009) An atypical role for collapsin response mediator protein 2 (CRMP-2) in neurotransmitter release via interaction with presynaptic voltage-gated calcium channels. J Biol Chem 284(45):31375–31390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Broeke Jurjen H, Roelandse M, Luteijn Maartje J, Boiko T, Matus A, Toonen RuudF, Verhage M (2010) Munc18 and Munc13 regulate early neurite outgrowth. Biol Cell 102(Pt 8):479–488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Buffenstein R (2005) The naked mole-rat: a new long-living model for human aging research. J Gerontol A Biol Sci Med Sci 60(11):1369–1377

    Article  PubMed  Google Scholar 

  8. Buffenstein R (2008) Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species. J Comp Physiol B 178(4):439–445

    Article  PubMed  Google Scholar 

  9. Buffenstein R, Edrey YH, Larsen P (2007) Animal models in aging research; a critical examination. Sourcebook of Models for Biomedical Research. M. Conn. USA. Humana Press, New York City, pp 499–506

    Google Scholar 

  10. Byk T, Dobransky T, Cifuentes-Diaz C, Sobel A (1996) Identification and molecular characterization of Unc-33-like phosphoprotein (Ulip), a putative mammalian homolog of the axonal guidance-associated unc-33 gene product. J Neurosci 16(2):688–701

    CAS  PubMed  Google Scholar 

  11. Castegna A, Aksenov M, Thongboonkerd V, Klein JB, Pierce WM, Booze R, Markesbery WR, Butterfield DA (2002) Proteomic identification of oxidatively modified proteins in Alzheimer’s disease brain. Part II: dihydropyrimidinase-related protein 2, alpha-enolase and heat shock cognate 71. J Neurochem 82(6):1524–1532

    Article  CAS  PubMed  Google Scholar 

  12. Charrier E, Reibel S, Rogemond V, Aguera M, Thomasset N, Honnorat J (2003) Collapsin response mediator proteins (CRMPs): involvement in nervous system development and adult neurodegenerative disorders. Mol Neurobiol 28(1):51–64

    Article  CAS  PubMed  Google Scholar 

  13. Cheng A, Hou Y, Mattson MP (2010) Mitochondria and neuroplasticity. ASN Neuro 2(5):e00045

    Article  PubMed  PubMed Central  Google Scholar 

  14. Craig TJ, Evans GJ, Morgan A (2003) Physiological regulation of Munc18/nSec1 phosphorylation on serine-313. J Neurochem 86(6):1450–1457

    Article  CAS  PubMed  Google Scholar 

  15. Dent EW, Gertler FB (2003) Cytoskeletal dynamics and transport in growth cone motility and axon guidance. Neuron 40(2):209–227

    Article  CAS  PubMed  Google Scholar 

  16. Di Domenico F, Coccia R, Butterfield DA, Perluigi M (2011) Circulating biomarkers of protein oxidation for Alzheimer disease: expectation within limits. Biochim Biophys Acta 1814:1785–1795.

    Article  PubMed  Google Scholar 

  17. Di Domenico F, Sultana R, Barone E, Perluigi M, Cini C, Mancuso C, Cai J, Pierce WM, Butterfield DA (2011) Quantitative proteomics analysis of phosphorylated proteins in the hippocampus of Alzheimer’s disease subjects. J Proteomics 74(7):1091–1103

    Article  PubMed  PubMed Central  Google Scholar 

  18. Edrey YH, Park TJ, Kang H, Biney A, Buffenstein R (2011) Endocrine function and neurobiology of the longest-living rodent, the naked mole-rat. Exp Gerontol 46(2–3):116–123

    Article  CAS  PubMed  Google Scholar 

  19. Endo M, Ohashi K, Sasaki Y, Goshima Y, Niwa R, Uemura T, Mizuno K (2003) Control of growth cone motility and morphology by LIM kinase and Slingshot via phosphorylation and dephosphorylation of cofilin. J Neurosci 23(7):2527–2537

    CAS  PubMed  Google Scholar 

  20. Evfratov SA, Smekalova EM, Golovin AV, Logvina NA, Zvereva MI, Dontsova OA (2014) Structural features of the telomerase RNA gene in the naked mole rat heterocephalus glaber. Acta Naturae 6(2):41–47

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Featherstone DE, Davis WS, Dubreuil RR, Broadie K (2001) Drosophila alpha- and beta-spectrin mutations disrupt presynaptic neurotransmitter release. J Neurosci 21(12):4215–4224

    CAS  PubMed  Google Scholar 

  22. Gomez-Isla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC, Parisi JE, Hyman BT (1997) Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol 41(1):17–24

    Article  CAS  PubMed  Google Scholar 

  23. Goshima Y, Nakamura F, Strittmatter P, Strittmatter SM (1995) Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33. Nature 376(6540):509–514

    Article  CAS  PubMed  Google Scholar 

  24. Gourlay CW, Ayscough KR (2005) The actin cytoskeleton: a key regulator of apoptosis and ageing? Nat Rev Mol Cell Biol 6(7):583–589

    Article  CAS  PubMed  Google Scholar 

  25. Gungabissoon RA, Bamburg JR (2003) Regulation of growth cone actin dynamics by ADF/cofilin. J Histochem Cytochem 51(4):411–420

    Article  CAS  PubMed  Google Scholar 

  26. Hagiwara A, Tanaka Y, Hikawa R, Morone N, Kusumi A, Kimura H, Kinoshita M (2011) Submembranous septins as relatively stable components of actin-based membrane skeleton. Cytoskeleton (Hoboken) 68(9):512–525

    Article  CAS  Google Scholar 

  27. Hensley K, Venkova K, Christov A, Gunning W, Park J (2011) Collapsin response mediator protein-2: an emerging pathologic feature and therapeutic target for neurodisease indications. Mol Neurobiol 43(3):180–191

    Article  CAS  PubMed  Google Scholar 

  28. Hulbert AJ, Pamplona R, Buffenstein R, Buttemer WA (2007) Life and death: metabolic rate, membrane composition, and life span of animals. Physiol Rev 87(4):1175–1213

    Article  CAS  PubMed  Google Scholar 

  29. Ju W, Li Q, Wilson SM, Brittain JM, Meroueh L, Khanna R (2013) SUMOylation alters CRMP2 regulation of calcium influx in sensory neurons. Channels (Austin) 7(3):153–159

    Article  CAS  Google Scholar 

  30. Kremer BE, Adang LA, Macara IG (2007) Septins regulate actin organization and cell-cycle arrest through nuclear accumulation of NCK mediated by SOCS7. Cell 130(5):837–850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lappalainen P, Drubin DG (1997) Cofilin promotes rapid actin filament turnover in vivo. Nature 388(6637):78–82

    Article  CAS  PubMed  Google Scholar 

  32. Larson J, Park TJ (2009) Extreme hypoxia tolerance of naked mole-rat brain. NeuroReport 20(18):1634–1637

    Article  PubMed  Google Scholar 

  33. Lewis KN, Mele J, Hornsby PJ, Buffenstein R (2012) Stress resistance in the naked mole-rat: the bare essentials—a mini-review. Gerontology 58(5):453–462

    Article  PubMed  PubMed Central  Google Scholar 

  34. Liang S, Mele J, Wu Y, Buffenstein R, Hornsby PJ (2010) Resistance to experimental tumorigenesis in cells of a long-lived mammal, the naked mole-rat (Heterocephalus glaber). Aging Cell 9(4):626–635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lin CH, Forscher P (1995) Growth cone advance is inversely proportional to retrograde F-actin flow. Neuron 14(4):763–771

    Article  CAS  PubMed  Google Scholar 

  36. Lowery LA, Van Vactor D (2009) The trip of the tip: understanding the growth cone machinery. Nat Rev Mol Cell Biol 10(5):332–343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Maciver SK, Hussey PJ (2002) The ADF/cofilin family actin-remodeling proteins. Genome Biol 3(5):3007

    Article  Google Scholar 

  38. Masliah E, Terry RD, DeTeresa RM, Hansen LA (1989) Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer disease. Neurosci Lett 103(2):234–239

    Article  CAS  PubMed  Google Scholar 

  39. McGeer E, McGeer P (1982) Neurotransmitters in normal aging. Geriatrics 1. Springer, Heidelberg, pp 263–282

    Google Scholar 

  40. Meberg PJ, Bamburg JR (2000) Increase in neurite outgrowth mediated by overexpression of actin depolymerizing factor. J Neurosci 20(7):2459–2469

    CAS  PubMed  Google Scholar 

  41. Minamide LS, Striegl AM, Boyle JA, Meberg PJ, Bamburg JR (2000) Neurodegenerative stimuli induce persistent ADF/cofilin-actin rods that disrupt distal neurite function. Nat Cell Biol 2(9):628–636

    Article  CAS  PubMed  Google Scholar 

  42. Misura KM, Scheller RH, Weis WI (2000) Three-dimensional structure of the neuronal-Sec1-syntaxin 1a complex. Nature 404(6776):355–362

    Article  CAS  PubMed  Google Scholar 

  43. Morgan CC, Mc Cartney AM, Donoghue MTA, Loughran NB, Spillane C, Teeling EC, O’Connell MJ (2013) Molecular adaptation of telomere associated genes in mammals. BMC Evol Biol 13:251

    Article  PubMed  PubMed Central  Google Scholar 

  44. Penz OK, Fuzik J, Kurek AB, Romanov R, Larson J, Park TJ, Harkany T, Keimpema E (2015) Protracted brain development in a rodent model of extreme longevity. Sci Rep 5:11592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Perez VI, Buffenstein R, Masamsetti V, Leonard S, Salmon AB, Mele J, Andziak B, Yang T, Edrey Y, Friguet B, Ward W, Richardson A, Chaudhuri A (2009) Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat. Proc Natl Acad Sci USA 106(9):3059–3064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Poon HF, Castegna A, Farr SA, Thongboonkerd V, Lynn BC, Banks WA, Morley JE, Klein JB, Butterfield DA (2004) Quantitative proteomics analysis of specific protein expression and oxidative modification in aged senescence-accelerated-prone 8 mice brain. Neuroscience 126(4):915–926

    Article  CAS  PubMed  Google Scholar 

  47. Raimondi A, Ferguson SM, Lou X, Armbruster M, Paradise S, Giovedi S, Messa M, Kono N, Takasaki J, Cappello V, O’Toole E, Ryan TA, De Camilli P (2011) Overlapping role of dynamin isoforms in synaptic vesicle endocytosis. Neuron 70(6):1100–1114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Rodriguez KA, Wywial E, Perez VI, Lambert AJ, Edrey YH, Lewis KN, Grimes K, Lindsey ML, Brand MD, Buffenstein R (2011) Walking the oxidative stress tightrope: a perspective from the naked mole-rat, the longest-living rodent. Curr Pharm Des 17(22):2290–2307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Seluanov A, Hine C, Azpurua J, Feigenson M, Bozzella M, Mao Z, Catania KC, Gorbunova V (2009) Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat. Proc Natl Acad Sci USA 106(46):19352–19357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Smillie KJ, Cousin MA (2005) Dynamin I phosphorylation and the control of synaptic vesicle endocytosis. Biochem Soc Symp 72:87–97

    Article  CAS  Google Scholar 

  51. Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, Fujimoto EK, Goeke NM, Olson BJ, Klenk DC (1985) Measurement of protein using bicinchoninic acid. Anal Biochem 150(1):76–85

    Article  CAS  PubMed  Google Scholar 

  52. Spiliotis ET, Hunt SJ, Hu Q, Kinoshita M, Nelson WJ (2008) Epithelial polarity requires septin coupling of vesicle transport to polyglutamylated microtubules. J Cell Biol 180(2):295–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sultana R, Boyd-Kimball D, Cai J, Pierce WM, Klein JB, Merchant M, Butterfield DA (2007) Proteomics analysis of the Alzheimer’s disease hippocampal proteome. J Alzheimers Dis 11(2):153–164

    CAS  PubMed  Google Scholar 

  54. Tada T, Simonetta A, Batterton M, Kinoshita M, Edbauer D, Sheng M (2007) Role of Septin cytoskeleton in spine morphogenesis and dendrite development in neurons. Curr Biol 17(20):1752–1758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Thongboonkerd V, McLeish KR, Arthur JM, Klein JB (2002) Proteomic analysis of normal human urinary proteins isolated by acetone precipitation or ultracentrifugation. Kidney Int 62(4):1461–1469

    Article  CAS  PubMed  Google Scholar 

  56. Toshima J, Toshima JY, Amano T, Yang N, Narumiya S, Mizuno K (2001) Cofilin phosphorylation by protein kinase testicular protein kinase 1 and its role in integrin-mediated actin reorganization and focal adhesion formation. Mol Biol Cell 12(4):1131–1145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Triplett JC, Swomley A, Kirk J, Lewis K, Orr M, Rodriguez K, Cai J, Klein JB, Buffenstein R, Butterfield DA (2015) Metabolic clues to salubrious longevity in the brain of the longest-lived rodent: the naked mole-rat. J Neurochem 134(3):538–550

    Article  CAS  PubMed  Google Scholar 

  58. Triplett JC, Tramutola A, Swomley A, Kirk J, Grimes K, Lewis K, Orr M, Rodriguez K, Cai J, Klein JB, Perluigi M, Buffenstein R, Butterfield DA (2015) Age-related changes in the proteostasis network in the brain of the naked mole-rat implications promoting healthy longevity. Biochim Biophys Acta 1852(10 Pt A):2213–2224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Uchida Y, Ohshima T, Sasaki Y, Suzuki H, Yanai S, Yamashita N, Nakamura F, Takei K, Ihara Y, Mikoshiba K, Kolattukudy P, Honnorat J, Goshima Y (2005) Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3β phosphorylation of CRMP2: implication of common phosphorylating mechanism underlying axon guidance and Alzheimer’s disease. Genes Cells 10(2):165–179

    Article  CAS  PubMed  Google Scholar 

  60. Xie Y, Vessey JP, Konecna A, Dahm R, Macchi P, Kiebler MA (2007) The GTP-binding protein Septin 7 is critical for dendrite branching and dendritic-spine morphology. Curr Biol 17(20):1746–1751

    Article  CAS  PubMed  Google Scholar 

  61. Yan Y, Winograd E, Viel A, Cronin T, Harrison SC, Branton D (1993) Crystal structure of the repetitive segments of spectrin. Science 262(5142):2027–2030

    Article  CAS  PubMed  Google Scholar 

  62. Yang B, Steegmaier M, Gonzalez LC Jr, Scheller RH (2000) nSec1 binds a closed conformation of syntaxin1A. J Cell Biol 148(2):247–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhang R, Zhang C, Zhao Q, Li D (2013) Spectrin: structure, function and disease. Sci China Life Sci 56(12):1076–1085

    Article  CAS  PubMed  Google Scholar 

  64. Zhao S, Lin L, Kan G, Xu C, Tang Q, Yu C, Sun W, Cai L, Xu C, Cui S (2014) High autophagy in the naked mole rat may play a significant role in maintaining good health. Cell Physiol Biochem 33(2):321–332

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Chemistry, University of Kentucky, Lexington, KY, 40506-0055, USA

    Judy C. Triplett, Aaron M. Swomley, Jessime Kirk & D. Allan Butterfield

  2. Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX, 78245, USA

    Kelly M. Grimes, Kaitilyn N. Lewis, Miranda E. Orr, Karl A. Rodriguez & Rochelle Buffenstein

  3. Department of Physiology, University of Texas Health Science Center, San Antonio, TX, 78245, USA

    Kelly M. Grimes, Miranda E. Orr, Karl A. Rodriguez & Rochelle Buffenstein

  4. Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, 78245, USA

    Kaitilyn N. Lewis

  5. Department of Nephrology and Proteomics Center, University of Louisville, Louisville, KY, 40202, USA

    Jian Cai & Jon B. Klein

  6. Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40506, USA

    D. Allan Butterfield

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  1. Judy C. Triplett
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Triplett, J.C., Swomley, A.M., Kirk, J. et al. Reaching Out to Send a Message: Proteins Associated with Neurite Outgrowth and Neurotransmission are Altered with Age in the Long-Lived Naked Mole-Rat. Neurochem Res 41, 1625–1634 (2016). https://doi.org/10.1007/s11064-016-1877-1

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  • DOI: https://doi.org/10.1007/s11064-016-1877-1

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