Abstract
Aberrant protein aggregation is mechanistically linked to late onset human neurodegenerations such as Parkinson’s, Huntington’s and Alzheimer’s diseases. Why these disorders emerge late in life is a principal enigma, however, recent results indicate that the aging process plays an active role in enabling their emergence. Perhaps the best characterized regulator of the aging process in worms, flies and mice is the Insulin/IGF-1 Signaling (IIS) pathway. In worms, IIS reduction results in activation of the FOXO-like transcription factor, DAF-16, resulting in enhanced stress resistance and longevity. The benefits associated with reduced IIS are also dependent upon another transcription factor, heat shock factor 1 (HSF-1). Reduced IIS also protects worms from proteotoxicity by regulating opposing activities: HSF-1 promotes disaggregation, while DAF-16 mediates protective active aggregation. The exploration of these mechanisms argues that the IIS enables the emergence of neurodegeneration late in life by reducing cellular capabilities to counter toxic protein aggregation. Here we review the recent studies and discuss the current themes and therapeutic potential of the IIS as a link between the aging process and late onset neurodegenerations
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References
Aguzzi A, Polymenidou M (2004) Mammalian prion biology: one century of evolving concepts. Cell 116(2): 313–327.
Amaducci L, Tesco G (1994) Aging as a major risk for degenerative diseases of the central nervous system. Curr Opin Neurol 7(4): 283–286.
Bandhyopadhyay U, Cuervo AM (2007) Chaperone-mediated autophagy in aging and neurodegeneration: Lessons from alpha-synuclein. Exp Gerontol 42(1–2): 120–128.
Bates G (2003) Huntingtin aggregation and toxicity in Huntington’s disease. Lancet 361(9369):1642–1644.
Behrends C, Langer CA, Boteva R, Bottcher UM, Stemp MJ et al. (2006) Chaperonin TRiC promotes the assembly of polyQ expansion proteins into nontoxic oligomers. Mol Cell 23(6): 887–897.
Bennett EJ, Bence NF, Jayakumar R, Kopito RR (2005) Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation. Mol Cell 17(3): 351–365.
Bluher M, Kahn BB, Kahn CR (2003) Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299(5606): 572–574.
Bosl B, Grimminger V, Walter S (2006) The molecular chaperone Hsp104 – a molecular machine for protein disaggregation. J Struct Biol 156(1): 139–148.
Carro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I (2002) Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med 8(12): 1390–1397.
Carro E, Trejo JL, Spuch C, Bohl D, Heard JM et al. (2006) Blockade of the insulin-like growth factor I receptor in the choroid plexus originates Alzheimer’s-like neuropathology in rodents: new cues into the human disease? Neurobiol Aging 27(11): 1618–1631.
Caughey B, Lansbury PT (2003) Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci 26: 267–298.
Chesebro B, Trifilo M, Race R, Meade-White K, Teng C et al. (2005) Anchorless prion protein results in infectious amyloid disease without clinical scrapie. Science 308(5727): 1435–1439.
Ciechanover A, Brundin P (2003) The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 40: 427–446.
Cohen E, Taraboulos A (2003) Scrapie-like prion protein accumulates in aggresomes of cyclosporin A-treated cells. EMBO J 22(3): 404–417.
Cohen E, Bieschke J, Perciavalle RM, Kelly JW, Dillin A (2006) Opposing activities protect against age-onset proteotoxicity. Science 313(5793): 1604–1610.
Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A et al. (2003) Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology 144(9):3799–3810.
Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305(5688): 1292–1295.
Gajdusek DC, Gibbs CJ, Jr. (1968) Slow, latent and temperate virus infections of the central nervous system. Research publications – association for research in nervous and mental disease 44:254–280.
Gidalevitz T, Ben-Zvi A, Ho KH, Brignull HR, Morimoto RI (2006) Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science 311(5766): 1471–1474.
Glover JR, Lindquist S (1998) Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell 94(1): 73–82.
Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8(2): 101–112.
Henderson ST, Johnson TE (2001) daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol 11(24): 1975–1980.
Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A et al. (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421(6919): 182–187.
Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S et al. (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425(6954): 191–196.
Hsu AL, Murphy CT, Kenyon C (2003) Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300(5622): 1142–1145.
Humbert S, Bryson EA, Cordelieres FP, Connors NC, Datta SR et al. (2002) The IGF-1/Akt pathway is neuroprotective in Huntington’s disease and involves Huntingtin phosphorylation by Akt. Dev Cell 2(6): 831–837.
Iwata N, Tsubuki S, Takaki Y, Shirotani K, Lu B et al. (2001) Metabolic regulation of brain Abeta by neprilysin. Science 292(5521): 1550–1552.
Kenyon C (2005) The plasticity of aging: insights from long-lived mutants. Cell 120(4): 449–460.
Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366(6454): 461–464.
Kopito RR, Ron D (2000) Conformational disease. Nat Cell Biol 2(11): E207–E209.
Lee RY, Hench J, Ruvkun G (2001) Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. Curr Biol 11(24): 1950–1957.
Lee VM, Trojanowski JQ (2006) Mechanisms of Parkinson’s disease linked to pathological alpha-synuclein: new targets for drug discovery. Neuron 52(1): 33–38.
Leissring MA, Farris W, Chang AY, Walsh DM, Wu X et al. (2003) Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 40(6): 1087–1093.
Link C (1995) Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans. Proc Natl Acad Sci USA 92(20): 9368–9372.
Liu XD, Liu PC, Santoro N, Thiele DJ (1997) Conservation of a stress response: human heat shock transcription factors functionally substitute for yeast HSF. EMBO J 16(21): 6466–6477.
Massey AC, Zhang C, Cuervo AM (2006) Chaperone-mediated autophagy in aging and disease. Curr Top Dev Biol 73: 205–235.
Morley JF, Morimoto RI (2004) Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. Mol Biol Cell 15(2): 657–664.
Morley JF, Brignull HR, Weyers JJ, Morimoto RI (2002) The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc Natl Acad Sci USA 99(16): 10417–10422.
Nollen EA, Salomons FA, Brunsting JF, Want JJ, Sibon OC et al. (2001) Dynamic changes in the localization of thermally unfolded nuclear proteins associated with chaperone-dependent protection. Proc Natl Acad Sci USA 98(21): 12038–12043.
Parker JA, Arango M, Abderrahmane S, Lambert E, Tourette C et al. (2005) Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nat Genet 37(4): 349–350.
Rabindran SK, Haroun RI, Clos J, Wisniewski J, Wu C (1993) Regulation of heat shock factor trimer formation: role of a conserved leucine zipper. Science 259(5092): 230–234.
Sarge KD, Murphy SP, Morimoto RI (1993) Activation of heat shock gene transcription by heat shock factor 1 involves oligomerization, acquisition of DNA-binding activity, and nuclear localization and can occur in the absence of stress. Mol Cell Biol 13(3): 1392–1407.
Selkoe DJ (2003) Folding proteins in fatal ways. Nature 426(6968): 900–904.
Shorter J, Lindquist S (2004) Hsp104 catalyzes formation and elimination of self-replicating Sup35 prion conformers. Science 304(5678): 1793–1797.
Silveira JR, Raymond GJ, Hughson AG, Race RE, Sim VL et al. (2005) The most infectious prion protein particles. Nature 437(7056): 257–261.
Singh V, Aballay A (2006) Heat-shock transcription factor (HSF)-1 pathway required for Caenorhabditis elegans immunity. Proc Natl Acad Sci USA 103(35): 13092–13097.
Timmons L, Fire A (1998) Specific interference by ingested dsRNA. Nature 395(6705): 854.
Tissenbaum HA, Ruvkun G (1998) An insulin-like signaling pathway affects both longevity and reproduction in Caenorhabditis elegans. Genetics 148(2): 703–717.
Tissenbaum HA, Guarente L (2001) Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410(6825): 227–230.
Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L et al. (2006) Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol 16(3): 296–300.
Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL et al. (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430(7000): 686–689.
Yamamoto A, Cremona ML, Rothman JE (2006) Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J Cell Biol 172(5): 719–731.
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Cohen, E., Dillin, A. (2008). Mechanistic Links Between Aging and Aggregation-Mediated Proteotoxicity: Role of HSF-1 and DAF-16. In: Asea, A.A., Brown, I.R. (eds) Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection. Heat Shock Proteins, vol 3. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-8231-3_17
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DOI: https://doi.org/10.1007/978-1-4020-8231-3_17
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