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Carrying Excess Baggage Can Slowdown Life: Protein Clearance Machineries That Go Awry During Aging and the Relevance of Maintaining Them

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Abstract

Cellular homeostasis is maintained by rapid and systematic cleansing of aberrant and aggregated proteins within cells. Neurodegenerative diseases (NDs) especially Parkinson’s and Alzheimer’s disease are known to be associated with multiple factors, most important being impaired clearance of aggregates, resulting in the accumulation of specific aggregated protein in the brain. Protein quality control (PQC) of proteostasis network comprises proteolytic machineries and chaperones along with their regulators to ensure precise operation and maintenance of proteostasis. Such regulatory factors coordinate among each other multiple functional aspects related to proteins, including their synthesis, folding, transport, and degradation. During aging due to inevitable endogenous and external stresses, sustaining a proteome balance is a challenging task. Such stresses decline the capacity of the proteostasis network compromising the proteome integrity, affecting the fundamental physiological processes including reproductive fitness of the organism. This review focuses on highlighting proteome-wide changes during aging and the strategies for proteostasis improvements. The possibility of augmenting the proteostasis network either via genetic or pharmacological interventions may be a promising strategy towards delaying age-associated pathological consequences due to proteome disbalance, thus promoting healthy aging and prolonged longevity.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Morton, J. P., Athineos, D., Kang, T., Lasitschka, F., Andrulis, M., Pascual, G., Morris, K. J., Khan, S., Jin, H., Dharmalingam, G., Snijders, A. P., Carroll, T., Capper, D., Pritchard, C., Inman, G. J., Longerich, T., Sansom, O. J., Benitah, A., Zender, L., and Gil, J. (2014) Europe PMC Funders Group Europe PMC Funders Author Manuscripts A complex secretory program orchestrated by the inflammasome controls paracrine senescence.15, 978–990

  2. Adam Bohnert K, Kenyon C (2017) A lysosomal switch triggers proteostasis renewal in the immortal C. elegans germ lineage. Nature 551:629–633

    PubMed Central  PubMed  Google Scholar 

  3. Aguilera-Gomez A, Rabouille C (2017) Membrane-bound organelles versus membrane-less compartments and their control of anabolic pathways in Drosophila. Dev Biol 428:310–317

    CAS  PubMed  Google Scholar 

  4. Alberti S, Hyman AA (2016) Are aberrant phase transitions a driver of cellular aging? BioEssays 38:959–968

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Alfaro IE, Albornoz A, Molina A, Moreno J, Cordero K, Criollo A, Budini M (2019) Chaperone mediated autophagy in the crosstalk of neurodegenerative diseases and metabolic disorders. Front Endocrinol (Lausanne) 10:1–13

    Google Scholar 

  6. Anguiano M, Nowak RJ, Lansbury PT (2002) Protofibrillar islet amyloid polypeptide permeabilizes synthetic vesicles by a pore-like mechanism that may be relevant to type II diabetes. Biochemistry 41:11338–11343

    CAS  PubMed  Google Scholar 

  7. Arbor A (2006) Autophagy: is it cancer’s friend or foe? Science 80(312):1160–1161

    Google Scholar 

  8. Arndt V, Rogon C, Höhfeld J (2007) To be, or not to be - molecular chaperones in protein degradation. Cell Mol Life Sci 64:2525–2541

    CAS  PubMed  Google Scholar 

  9. Badadani M (2012) Autophagy mechanism, regulation, functions, and disorders. ISRN Cell Biol 2012:1–11

    Google Scholar 

  10. Balch WE, Morimoto RI, Dillin A, Kelly JW (2008) Adapting proteostasis for disease intervention. Science 80(319):916–919

    Google Scholar 

  11. Balchin, D., Hayer-Hartl, M., and Hartl, F. U. (2016) In vivo aspects of protein folding and quality control. Science (80-. ). https://doi.org/10.1126/science.aac4354

  12. Bandyopadhyay U, Kaushik S, Varticovski L, Cuervo AM (2008) The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane. Mol Cell Biol 28:5747–5763

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Baranczak A, Kelly JW (2016) A current pharmacologic agent versus the promise of next generation therapeutics to ameliorate protein misfolding and/or aggregation diseases. Curr Opin Chem Biol 32:10–21

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Bergamini E, Cavallini G, Donati A, Gori Z (2004) The role of macroautophagy in the ageing process, anti-ageing intervention and age-associated diseases. Int J Biochem Cell Biol 36:2392–2404

    CAS  PubMed  Google Scholar 

  15. Bingol B, Wang CF, Arnott D, Cheng D, Peng J, Sheng M (2010) Autophosphorylated CaMKIIα acts as a scaffold to recruit proteasomes to dendritic spines. Cell 140:567–578

    CAS  PubMed  Google Scholar 

  16. Bogyo M, Gaczynska M, Ploegh HL (1997) Proteasome inhibitors and antigen presentation. Biopolymers 43:269–280

    CAS  PubMed  Google Scholar 

  17. Brandt T, Mourier A, Tain LS, Partridge L, Larsson NG, Kühlbrandt W (2017) Changes of mitochondrial ultrastructure and function during ageing in mice and Drosophila. Elife 6:1–19

    Google Scholar 

  18. Bronstein JM, Chou AP (2006) Peripheral proteasome and caspase activity in Parkinson disease and Alzheimer disease [1]. Neurology 67:182

    PubMed  Google Scholar 

  19. Buchan JR, Kolaitis RM, Taylor JP, Parker R (2013) XEukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell 153:1461

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Cadonic C, Sabbir MG, Albensi BC (2016) Mechanisms of Mitochondrial dysfunction in Alzheimer’s disease. Mol Neurobiol 53:6078–6090

    CAS  PubMed  Google Scholar 

  21. Carra S, Alberti S, Arrigo PA, Benesch JL, Benjamin IJ, Boelens W, Bartelt-Kirbach B, Brundel BJJM, Buchner J, Bukau B, Carver JA, Ecroyd H, Emanuelsson C, Finet S, Golenhofen N, Goloubinoff P, Gusev N, Haslbeck M, Hightower LE, Kampinga HH, Klevit RE, Liberek K, Mchaourab HS, McMenimen KA, Poletti A, Quinlan R, Strelkov SV, Toth ME, Vierling E, Tanguay RM (2017) The growing world of small heat shock proteins: from structure to functions. Cell Stress Chaperones 22:601–611

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Chang HW, Kwon S, Kim H, Lee K, Kim M, Moon T, Baek S (2002) Platelet-activating factor acetylhydrolase activity in cerebrospinal fluid of children with acute systemic or neurological illness. Ann Neurol 51:760–763

    CAS  PubMed  Google Scholar 

  23. Chauhan R, Chen KF, Kent BA, Crowther DC (2017) Central and peripheral circadian clocks and their role in Alzheimer’s disease. DMM Dis Model Mech 10:1187–1199

    CAS  PubMed  Google Scholar 

  24. Chong Y (1997) Effect of a carboxy-terminal fragment of the Alzheimer’s amyloid precursor protein on expression of proinflammatory cytokines in rat glial cells. Life Sci 61:2323–2333

    CAS  PubMed  Google Scholar 

  25. Chee Yeun Chung,1* Vikram Khurana,1,2* Pavan K. Auluck,1,3 Daniel F. Tardiff,1 Joseph R. Mazzulli,2 Frank Soldner,1 Valeriya Baru,1,4 Yali Lou,1,4 Yelena Freyzon,1 Sukhee Cho,5 Alison E. Mungenast,5 Julien Muffat,1 Maisam Mitalipova,1 Michael D. Pluth,6 N, S. L. (2010) Identification and rescue of a-synuclein toxicity in Parkinson patient–derived neurons. 342, 983–987

  26. Colledge M, Snyder EM, Crozier RA, Soderling JA, Jin Y, Langeberg LK, Lu H, Bear MF, Scott JD (2003) Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression. Neuron 40:595–607

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Cookson MR (2012) Parkinsonism due to mutations in PINK1, Parkin, and DJ-1 and oxidative stress and mitochondrial pathways. Cold Spring Harb Perspect Med 2:1–11

    Google Scholar 

  28. Cuervo AM (2004) Autophagy: in sickness and in health. Trends Cell Biol 14:70–77

    PubMed  Google Scholar 

  29. Daniel MW, Kalfalah F, Florea AM, Sass S, Kruse F, Rieder V, Tigges J, Fritsche E, Krutmann J, Busch H, Meyer HE, Boege F, Theis F, Reifenberger G (2014) Proteome-wide analysisreveals an age-associated cellular phenotype. Aging 6:856–872

    Google Scholar 

  30. Demarest SJ, Martinez-Yamout M, Chung J, Chen H, Xu W, Jane Dyson H, Evans RM, Wright PE (2002) Mutual synergistic folding in recruitment of cbp/p300 by p160 nuclear receptor coactivators. Nature 415:549–553

    CAS  PubMed  Google Scholar 

  31. Di Bartolomeo S, Corazzari M, Nazio F, Oliverio S, Lisi G, Antonioli M, Pagliarini V, Matteoni S, Fuoco C, Giunta L, D’Amelio M, Nardacci R, Romagnoli A, Piacentini M, Cecconi F, Fimia GM (2010) The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. J Cell Biol 191:155–168

    PubMed Central  PubMed  Google Scholar 

  32. Dice, J. F. UNIT 11 lysosomal pathways of protein degradation

  33. Dick FD (2006) Parkinson’s disease and pesticide exposures. Br Med Bull 79–80:219–231

    PubMed  Google Scholar 

  34. Dikic I (2017) Proteasomal and autophagic degradation systems. Annu Rev Biochem 86:193–224

    CAS  PubMed  Google Scholar 

  35. Dunker AK, Silman I, Uversky VN, Sussman JL (2008) Function and structure of inherently disordered proteins. Curr Opin Struct Biol 18:756–764

    CAS  PubMed  Google Scholar 

  36. Dunn WA (1990) Studies on the mechanisms of autophagy: maturation of the autophagic vacuole. J Cell Biol 110:1935–1945

    CAS  PubMed  Google Scholar 

  37. Ehlers MD (2003) Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nat Neurosci 6:231–242

    CAS  PubMed  Google Scholar 

  38. Esser C, Alberti S, Höhfeld J (2004) Cooperation of molecular chaperones with the ubiquitin/proteasome system. Biochim Biophys Acta - Mol Cell Res 1695:171–188

    CAS  Google Scholar 

  39. Etlinger JD, Goldberg AL (1977) A soluble ATP dependent proteolytic system responsible for the degradation of abnormal proteins in reticulocytes. Proc Natl Acad Sci U S A 74:54–58

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Faragher, R. G. A., McArdle, A., Willows, A., and Ostler, E. L. (2017) Senescence in the aging process. F1000Research. 6, 1–9

  41. Faust JR, Luskey KL, Chin DJ, Goldstein JL, Brown MS (1982) Regulation of synthesis and degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase by low density lipoprotein and 25-hydroxycholesterol in UT-1 cells. Proc Natl Acad Sci U S A 79:5205–5209

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Fearon RMP, Reiss D, Leve LD, Shaw DS, Scaramella LV, Ganiban JM, Neiderhiser JM (2015) Increased proteasome activity determines human embryonic stem cell identity. Dev Psychopathol 27:1251–1265

    PubMed  Google Scholar 

  43. Feng Y, He D, Yao Z, Klionsky DJ (2014) The machinery of macroautophagy. Cell Res 24:24–41

    CAS  PubMed  Google Scholar 

  44. Feng T, Tammineni P, Agrawal C, Jeong YY, Cai Q (2017) Autophagy-mediated regulation of BACE1 protein trafficking and degradation. J Biol Chem 292:1679–1690

    CAS  PubMed  Google Scholar 

  45. Ganassi M, Mateju D, Bigi I, Mediani L, Poser I, Lee HO, Seguin SJ, Morelli FF, Vinet J, Leo G, Pansarasa O, Cereda C, Poletti A, Alberti S, Carra S (2016) A surveillance function of the HSPB8-BAG3-HSP70 chaperone complex ensures stress granule integrity and dynamism. Mol Cell 63:796–810

    CAS  PubMed  Google Scholar 

  46. Gao W, Ding WX, Stolz DB, Yin XM (2008) Induction of macroautophagy by exogenously introduced calcium. Autophagy 4:754–761

    CAS  PubMed  Google Scholar 

  47. García-Cerro S, Rueda N, Vidal V, Lantigua S, Martínez-Cué C (2017) Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer’s disease phenotypes. Neurobiol Dis 106:76–88

    PubMed  Google Scholar 

  48. F Gasset-rosa C Chillon-marinas A Goginashvili S Atwal JW Artates R Tabet VC Wheeler G Anne DW Cleveland C Lagier-tourenne L Jolla L Jolla MG Hospital MG Hospital S Burnham P Medical L Jolla 2018 HHS Public Access 94 48 57

  49. Geisler S, Holmström KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W (2010) PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 12:119–131

    CAS  PubMed  Google Scholar 

  50. Ghaemmaghami S et al (2003) Global analysis of protein expression in yeast. Nature 425:737–741

    CAS  PubMed  Google Scholar 

  51. Gidalevitz T, Ben-Zvi A, Ho KH, Brignull HR, Morimoto RI (2006) Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science 311:1471–1474

    CAS  PubMed  Google Scholar 

  52. -. Glover, D., Tajima, S., Yamamoto, A., Borgstrom, B., Brockman, L., Schotz, C., Guidoni, A., Caro, J. De, Crea, R., Acids, N., Sanger, F., Nicklen, S., Sarnbrook, J., and Harbor, C. S. (1986) Hiroshi mori,. 329, 0–3

  53. Godin JD, Creppe C, Laguesse S, Nguyen L (2016) Emerging roles for the unfolded protein response in the developing nervous system. Trends Neurosci 39:394–404

    CAS  PubMed  Google Scholar 

  54. Grice GL, Nathan JA (2016) The recognition of ubiquitinated proteins by the proteasome. Cell Mol Life Sci 73:3497–3506

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Groll M, Bajorek M, Köhler A, Moroder L, Rubin DM, Huber R, Glickman MH, Finley D (2000) A gated channel into the proteasome core particle. Nat Struct Biol 7:1062–1067

    CAS  PubMed  Google Scholar 

  56. Gutiérrez-Casado E, Khraiwesh H, López-Domínguez JA, Montero-Guisado J, López-Lluch G, Navas P, De Cabo R, Ramsey JJ, González-Reyes JA, Villalba JM (2019) The impact of aging, calorie restriction and dietary fat on autophagy markers and mitochondrial ultrastructure and dynamics in mouse skeletal muscle. J Gerontol. – Ser A Biol Sci Med Sci 74:760–769

    Google Scholar 

  57. Hara, K., Maruki, Y., Long, X., Yoshino, K. ichi, Oshiro, N., Hidayat, S., Tokunaga, C., Avruch, J., and Yonezawa, K. (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 110, 177–189

  58. Hasson SA, Kane LA, Yamano K, Huang CH, Sliter DA, Buehler E, Wang C, Heman-Ackah SM, Hessa T, Guha R, Martin SE, Youle RJ (2013) High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy. Nature 504:291–295

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Hetz C, Mollereau B (2014) Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat Rev Neurosci 15:233–249

    CAS  PubMed  Google Scholar 

  60. Hipp MS, Kasturi P, Hartl FU (2019) The proteostasis network and its decline in ageing. Nat Rev Mol Cell Biol 20:421–435

    CAS  PubMed  Google Scholar 

  61. Hoozemans JJM, Van Haastert ES, Nijholt DAT, Rozemuller AJM, Scheper W (2012) Activation of the unfolded protein response is an early event in Alzheimer’s and Parkinson’s disease. Neurodegener Dis 10:212–215

    CAS  PubMed  Google Scholar 

  62. Jenkinson EM, Rehman AU, Walsh T, Clayton-Smith J, Lee K, Morell RJ, Drummond MC, Khan SN, Naeem MA, Rauf B, Billington N, Schultz JM, Urquhart JE, Lee MK, Berry A, Hanley NA, Mehta S, Cilliers D, Clayton PE, Kingston H, Smith MJ, Warner TT, Black GC, Trump D, Davis JRE, Ahmad W, Leal SM, Riazuddin S, King MC, Friedman TB, Newman WG (2013) Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease. Am J Hum Genet 92:605–613

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Jiao W, Li P, Zhang J, Zhang H, Chang Z (2005) Small heat-shock proteins function in the insoluble protein complex. Biochem Biophys Res Commun 335:227–231

    CAS  PubMed  Google Scholar 

  64. Kedersha N, Ivanov P, Anderson P (2013) Stress granules and cell signaling: more than just a passing phase? Trends Biochem. Science 38:494–506

    CAS  Google Scholar 

  65. Kenyon CJ (2010) The genetics of ageing. Nature 464:504–512

    CAS  PubMed  Google Scholar 

  66. Kenyon C (2011) The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing. Philos Trans R Soc B Biol Sci 366:9–16

    CAS  Google Scholar 

  67. Kim YE, Hosp F, Frottin F, Ge H, Mann M, Hayer-Hartl M, Hartl FU (2016) Soluble oligomers of polyQ-expanded huntingtin target a multiplicity of key cellular factors. Mol Cell 63:951–964

    CAS  PubMed  Google Scholar 

  68. Kirstein-Miles J, Scior A, Deuerling E, Morimoto RI (2013) The nascent polypeptide-associated complex is a key regulator of proteostasis. EMBO J 32:1451–1468

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Kisselev AF, Goldberg AL (2001) Proteasome inhibitors: from research tools to drug candidates. Chem Biol 8:739–758

    CAS  PubMed  Google Scholar 

  70. Kitada T, Pisani A, Karouani M, Haburcak M, Martella G, Tscherter A, Platania P, Wu B, Pothos EN, Shen J (2009) Impaired dopamine release and synaptic plasticity in the striatum of Parkin-/- mice. J Neurochem 110:613–621

    CAS  PubMed  Google Scholar 

  71. Kitamura A, Inada N, Kubota H, Matsumoto G, Kinjo M, Morimoto RI, Nagata K (2014) Dysregulation of the proteasome increases the toxicity of ALS-linked mutant SOD1. Genes Cells 19:209–224

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Klaips CL, Jayaraj GG, Hartl FU (2018) Pathways of cellular proteostasis in aging and disease. J Cell Biol 217:51–63

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Kostova KK, Hickey KL, Osuna BA, Hussmann JA, Frost A, Weinberg DE, Weissman JS (2017) CAT-tailing as a fail-safe mechanism for efficient degradation of stalled nascent polypeptides. Science 80(357):414–417

    Google Scholar 

  74. Kraytsberg Y, Kudryavtseva E, McKee AC, Geula C, Kowall NW, Khrapko K (2006) Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet 38:518–520

    CAS  PubMed  Google Scholar 

  75. Kulak NA, Geyer PE, Mann M (2017) Loss-less nano-fractionator for high sensitivity, high coverage proteomics. Mol Cell Proteomics 16:694–705

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Kumar KR, Weissbach A, Heldmann M, Kasten M, Tunc S, Sue CM, Svetel M, Kostić VS, Segura-Aguilar J, Ramirez A, Simon DK, Vieregge P, Münte TF, Hagenah J, Klein C, Lohmann K (2012) Frequency of the D620N mutation in VPS35 in Parkinson disease. Arch Neurol 69:1360–1364

    PubMed  Google Scholar 

  77. Kundra R, Ciryam P, Morimoto RI, Dobson CM, Vendruscolo M (2017) Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease. Proc Natl Acad Sci USA 114:E5703–E5711

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Kunzt JB, Schwarz H, Mayer A (2004) Determination of four sequential Stages during microautophagy in vitro. J Biol Chem 279:9987–9996

    Google Scholar 

  79. Kuzuhara S, Mori H, Izumiyama N, Yoshimura M, Ihara Y (1988) Lewy bodies are ubiquitinated. Acta Neuropathol 75:345–353

    CAS  PubMed  Google Scholar 

  80. Labbadia J, Morimoto RI (2015) Repression of the heat shock response is a programmed event at the onset of reproduction. Mol Cell 59:639–650

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Labbadia J, Morimoto RI (2015) The biology of proteostasis in aging and disease. Annu Rev Biochem 84:435–464

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Laguesse S, Creppe C, Nedialkova DD, Prévot PP, Borgs L, Huysseune S, Franco B, Duysens G, Krusy N, Lee G, Thelen N, Thiry M, Close P, Chariot A, Malgrange B, Leidel SA, Godin JD, Nguyen L (2015) A dynamic unfolded protein response contributes to the control of cortical neurogenesis. Dev Cell 35:553–567

    CAS  PubMed  Google Scholar 

  83. Lamark, T., and Johansen, T. (2012) Aggrephagy: selective disposal of protein aggregates by macroautophagy. Int. J. Cell Biol. https://doi.org/10.1155/2012/736905

  84. Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT (2002) Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418:291

    CAS  PubMed  Google Scholar 

  85. Lechler MC, Crawford ED, Groh N, Widmaier K, Jung R, Kirstein J, Trinidad JC, Burlingame AL, David DC (2017) Reduced insulin/IGF-1 signaling restores the dynamic properties of key stress granule proteins during aging. Cell Rep 18:454–467

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Lee C, Kim H, Bardwell JCA (2018) Electrostatic interactions are important for chaperone–client interaction in vivo. Microbiol (United Kingdom) 164:992–997

    CAS  Google Scholar 

  87. Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Björklund A, Widner H, Revesz T, Lindvall O, Brundin P (2008) Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med 14:501–503

    CAS  PubMed  Google Scholar 

  88. Li WW, Li J, Bao JK (2012) Microautophagy: lesser-known self-eating. Cell Mol Life Sci 69:1125–1136

    CAS  PubMed  Google Scholar 

  89. Liang Y (2019) Emerging concepts and functions of autophagy as a regulator of synaptic components and plasticity. Cells 8:34

    CAS  PubMed Central  Google Scholar 

  90. Liang YT, Sigrist S (2018) Autophagy and proteostasis in the control of synapse aging and disease. Curr Opin Neurobiol 48:113–121

    CAS  PubMed  Google Scholar 

  91. Liang V, Ullrich M, Lam H, Chew YL, Banister S, Song X, Zaw T, Kassiou M, Götz J, Nicholas HR (2014) Altered proteostasis in aging and heat shock response in C. elegans revealed by analysis of the global and de novo synthesized proteome. Cell Mol Life Sci 71:3339–3361

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Liu Q, D’Silva P, Walter W, Marszalek J, Craig EA (2003) Regulated cycling of mitochondrial Hsp70 at the protein import channel. Science 80(300):139–141

    Google Scholar 

  93. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194

    PubMed Central  PubMed  Google Scholar 

  94. Lu K, den Brave F, Jentsch S (2017) Pathway choice between proteasomal and autophagic degradation. Autophagy 13:1799–1800

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Lu K, Den Brave F, Jentsch S (2017) Receptor oligomerization guides pathway choice between proteasomal and autophagic degradation. Nat Cell Biol 19:732–739

    CAS  PubMed  Google Scholar 

  96. Luoma P, Melberg A, Rinne JO, Kaukonen JA, Nupponen NN, Chalmers RM, Oldfors PA, Rautakorpi I, Peltonen PL, Majamaa PK, Somer H, Suomalainen A (2004) Parkinsonism, premature menopause, and mitochondrial DNA polymerase γ mutations: clinical and molecular genetic study. Lancet 364:875–882

    CAS  PubMed  Google Scholar 

  97. Mackiewicz M, Shockley KR, Romer MA, Galante RJ, Zimmerman JE, Naidoo N, Baldwin DA, Jensen ST, Churchill GA, Pack AI (2007) Macromolecule biosynthesis: a key function of sleep. Physiol Genomics 31:441–457

    CAS  PubMed  Google Scholar 

  98. Manderville RA, Wetmore SD (2017) Mutagenicity of ochratoxin A: role for a carbon-linked C8-deoxyguanosine adduct? J Agric Food Chem 65:7097–7105

    CAS  PubMed  Google Scholar 

  99. Martínez-Cué C, Rueda N (2020) Cellular senescence in neurodegenerative diseases. Front Cell Neurosci. https://doi.org/10.3389/fncel.2020.00016

    Article  PubMed Central  PubMed  Google Scholar 

  100. Matai L, Sarkar GC, Chamoli M, Malik Y, Kumar SS, Rautela U, Jana NR, Chakraborty K, Mukhopadhyay A (2019) Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis. Proc Natl Acad Sci USA 116:17383–17392

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Mateju D, Franzmann TM, Patel A, Kopach A, Boczek EE, Maharana S, Lee HO, Carra S, Hyman AA, Alberti S (2017) An aberrant phase transition of stress granules triggered by misfolded protein and prevented by chaperone function. EMBO J 36:1669–1687

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Mimura N, Yuasa S, Soma M, Jin H, Kimura K, Goto S, Koseki H, Aoe T (2008) Altered quality control in the endoplasmic reticulum causes cortical dysplasia in knock-in mice expressing a mutant BiP. Mol Cell Biol 28:293–301

    CAS  PubMed  Google Scholar 

  103. Minard AY, Wong MKL, Chaudhuri R, Tan SX, Humphrey SJ, Parker BL, Yang JY, Laybutt DR, Cooney GJ, Coster ACF, Stöckli J, James DE (2016) Hyperactivation of the insulin signaling pathway improves intracellular proteostasis by coordinately up-regulating the proteostatic machinery in adipocytes. J Biol Chem 291:25629–25640

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Moehle EA, Shen K, Dillin A (2019) Mitochondrial proteostasis in the context of cellular and organismal health and aging. J Biol Chem 294:5396–5407

    CAS  PubMed  Google Scholar 

  105. Mohrin M, Shin J, Liu Y, Brown K, Luo H, Xi Y, Haynes CM, Chen D (2015) A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 80(347):1374–1377

    Google Scholar 

  106. Moll L, Roitenberg N, Bejerano-Sagie M, Boocholez H, Marques FC, Volovik Y, Elami T, Siddiqui AA, Grushko D, Biram A, Lampert B, Achache H, Ravid T, Tzur YB, Cohen E (2018) The insulin/IGF signaling cascade modulates SUMOylation to regulate aging and proteostasis in caenorhabditis elegans. Elife 7:1–29

    Google Scholar 

  107. Morrow G, Tanguay RM (2015) Drosophila melanogaster Hsp22: a mitochondrial small heat shock protein influencing the aging process. Front Genet 6:1–7

    CAS  Google Scholar 

  108. Moujaber O, Mahboubi H, Kodiha M, Bouttier M, Bednarz K, Bakshi R, White J, Larose L, Colmegna I, Stochaj U (2017) Dissecting the molecular mechanisms that impair stress granule formation in aging cells. Biochim Biophys Acta - Mol Cell Res 1864:475–486

    CAS  PubMed  Google Scholar 

  109. Nargund A, Pellegrino MW, Fiorese CJ, Baker BM, Haynes CM (2012) Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 80(337):587–590

    Google Scholar 

  110. Nargund AM, Fiorese CJ, Pellegrino MW, Deng P, Haynes CM (2015) Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPRmt. Mol Cell 58:123–133

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, MacKenzie IRA (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–2931

    PubMed Central  PubMed  Google Scholar 

  112. Nikoletopoulou V, Sidiropoulou K, Kallergi E, Dalezios Y, Tavernarakis N (2017) Modulation of autophagy by BDNF underlies synaptic plasticity. Cell Metab 26:230-242.e5

    CAS  PubMed  Google Scholar 

  113. Opoku-Nsiah KA, Gestwicki JE (2018) Aim for the core: suitability of the ubiquitin-independent 20S proteasome as a drug target in neurodegeneration. Transl Res 198:48–57

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Ori A, Toyama BH, Harris MS, Bock T, Iskar M, Bork P, Ingolia NT, Hetzer MW, Beck M (2015) Integrated transcriptome and proteome analyses reveal organ-specific proteome deterioration in old rats. Cell Syst 1:224–237

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Ounallah-Saad H, Sharma V, Edry E, Rosenblum K (2014) Genetic or pharmacological reduction of PERK enhances cortical-dependent taste learning. J Neurosci 34:14624–14632

    PubMed Central  PubMed  Google Scholar 

  116. Paxman R, Plate L, Blackwood EA, Glembotski C, Powers ET, Wiseman RL, Kelly JW (2018) Pharmacologic ATF6 activating compounds are metabolically activated to selectively modify endoplasmic reticulum proteins. Elife 7:1–23

    Google Scholar 

  117. Pellegrino MW, Haynes CM (2015) Mitophagy and the mitochondrial unfolded protein response in neurodegeneration and bacterial infection. BMC Biol 13:1–9

    CAS  Google Scholar 

  118. Abhisek Mukherjee1, Diego Morales-Scheihing1, 2, Peter C. Butler3, and C. S. (2015) Type 2 diabetes as a misfolding disease. 155 3 12

  119. Picotti P et al (2013) A complete mass-spectrometric map of the yeast proteome applied to quantitative trait analysis. Nature 494:266–270

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Powers ET, Morimoto RI, Dillin A, Kelly JW, Balch WE (2009) Biological and chemical approaches to diseases of proteostasis deficiency. Annu Rev Biochem 78:959–991

    CAS  PubMed  Google Scholar 

  121. Protter DSW, Parker R (2016) Principles and properties of stress granules. Trends Cell Biol 26:668–679

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Rallis A, Navarro JA, Rass M, Hu A, Birman S, Schneuwly S, Thérond PP (2020) Hedgehog signaling modulates glial proteostasis and lifespan. Cell Rep 30:2627-2643.e5

    CAS  PubMed  Google Scholar 

  123. Ramachandran KV, Margolis SS (2017) A mammalian nervous-system-specific plasma membrane proteasome complex that modulates neuronal function. Nat Struct Mol Biol 24:419–430

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Ramachandran KV, Fu JM, Schaffer TB, Na CH, Delannoy M, Margolis SS (2018) Activity-dependent degradation of the nascentome by the neuronal membrane proteasome. Mol Cell 71:169-177.e6

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Rangaraju S, Verrier JD, Madorsky I, Nicks J, Dunn WA, Notterpek L (2010) Rapamycin activates autophagy and improves myelination in explant cultures from neuropathic mice. J Neurosci 30:11388–11397

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Ravikumar B, Futter M, Jahreiss L, Korolchuk VI, Lichtenberg M, Luo S, Massey DCO, Menzies FM, Narayanan U, Renna M, Jimenez-Sanchez M, Sarkar S, Underwood B, Winslow A, Rubinsztein DC (2009) Mammalian macroautophagy at a glance. J Cell Sci 122:1707–1711

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Reis-Rodrigues P, Czerwieniec G, Peters TW, Evani US, Alavez S, Gaman EA, Vantipalli M, Mooney SD, Gibson BW, Lithgow GJ, Hughes RE (2012) Proteomic analysis of age-dependent changes in protein solubility identifies genes that modulate lifespan. Aging Cell 11:120–127

    CAS  PubMed  Google Scholar 

  128. Riek R, Eisenberg DS (2016) The activities of amyloids from a structural perspective. Nature 539:227–235

    PubMed  Google Scholar 

  129. Ross Buchan J (2014) MRNP granules assembly, function, and connections with disease. RNA Biol 11:1019–1030

    PubMed Central  PubMed  Google Scholar 

  130. Rousseau A, Bertolotti A (2016) An evolutionarily conserved pathway controls proteasome homeostasis. Nature 536:184–189

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Rubinsztein DC, Mariño G, Kroemer G (2011) Autophagy and aging. Cell 146:682–695

    CAS  PubMed  Google Scholar 

  132. Saez I, Vilchez D (2014) The mechanistic links between proteasome activity, aging and agerelated diseases. Curr Genomics 15:38–51

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Sahu R, Kaushik S, Clement CC, Cannizzo ES, Scharf B, Follenzi A, Potolicchio I, Nieves E, Cuervo AM, Santambrogio L (2011) Microautophagy of cytosolic proteins by late endosomes. Dev Cell 20:131–139

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Sauer RT, Baker TA (2011) AAA+ proteases: ATP-fueled machines of protein destruction. Annu Rev Biochem 80:587–612

    CAS  PubMed  Google Scholar 

  135. Schmidt M, Finley D (2014) Regulation of proteasome activity in health and disease. Biochim Biophys Acta - Mol Cell Res 1843:13–25

    CAS  Google Scholar 

  136. Schubert U, Antón LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR (2000) Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404:770–774

    CAS  PubMed  Google Scholar 

  137. Seaman MNJ (2004) Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer. J Cell Biol 165:111–122

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Şentürk M, Lin G, Zuo Z, Mao D, Watson E, Mikos AG, Bellen HJ (2019) Ubiquilins regulate autophagic flux through mTOR signalling and lysosomal acidification. Nat Cell Biol 21:384–396

    PubMed Central  PubMed  Google Scholar 

  139. Shemesh N, Ben-Zvi A (2018) No excess baggage: new life starts with a clean slate. Mol Cell 69:163–164

    CAS  PubMed  Google Scholar 

  140. Shpilka T, Haynes CM (2018) The mitochondrial UPR: mechanisms, physiological functions and implications in ageing. Nat Rev Mol Cell Biol 19:109–120

    CAS  PubMed  Google Scholar 

  141. Song J, Herrmann JM, Becker T (2021) Quality control of the mitochondrial proteome. Nat Rev Mol Cell Biol 22:54–70

    CAS  PubMed  Google Scholar 

  142. Stickgold R, Walker MP (2007) Sleep-dependent memory consolidation and reconsolidation. Sleep Med 8:331–343

    PubMed Central  PubMed  Google Scholar 

  143. Tabara K, Iwata Y, Koizumi N (2018) The unfolded protein response. Methods Mol Biol 1691:223–230

    CAS  PubMed  Google Scholar 

  144. Taylor RC, Dillin A (2011) Aging as an event of proteostasis collapse. Cold Spring Harb Perspect Biol 3:1–17

    Google Scholar 

  145. Terlecky SR, Chiang HL, Olson TS, Dice JF (1992) Protein and peptide binding and stimulation of in vitro lysosomal proteolysis by the 73-kDa heat shock cognate protein. J Biol Chem 267:9202–9209

    CAS  PubMed  Google Scholar 

  146. RE Thomas LA Andrews JL Burman WY Lin LJ Pallanck 2014 PINK1-Parkin pathway activity is regulated by degradation of PINK1 in the mitochondrial matrix PLoS Genet https://doi.org/10.1371/journal.pgen.1004279

  147. Thrower JS, Hoffman L, Rechsteiner M, Pickart CM (2000) Recognition of the polyubiquitin proteolytic signal. EMBO J 19:94–102

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Tononi G, Cirelli C (2003) Sleep and synaptic homeostasis: a hypothesis. Brain Res Bull 62:143–150

    PubMed  Google Scholar 

  149. Tsaytler P, Harding HP, Ron D, Bertolotti A (2011) Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science 80(332):91–94

    Google Scholar 

  150. Urra H, Dufey E, Lisbona F, Rojas-Rivera D, Hetz C (2013) When ER stress reaches a dead end. Biochim Biophys Acta - Mol Cell Res 1833:3507–3517

    CAS  Google Scholar 

  151. Urra H, Henriquez DR, Cánovas J, Villarroel-Campos D, Carreras-Sureda A, Pulgar E, Molina E, Hazari YM, Limia CM, Alvarez-Rojas S, Figueroa R, Vidal RL, Rodriguez DA, Rivera CA, Court FA, Couve A, Qi L, Chevet E, Akai R, Iwawaki T, Concha ML, Glavic Á, Gonzalez-Billault C, Hetz C (2018) IRE1α governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A. Nat Cell Biol 20:942–953

    CAS  PubMed  Google Scholar 

  152. Van Deursen JM (2014) The role of senescent cells in ageing. Nature 509:439–446

    PubMed Central  PubMed  Google Scholar 

  153. Velarde MC, Menon R (2016) Positive and negative effects of cellular senescence during female reproductive aging and pregnancy. J Endocrinol 230:R59–R76

    CAS  PubMed  Google Scholar 

  154. Veljanovski V, Batoko H (2014) Selective autophagy of non-ubiquitylated targets in plants: looking for cognate receptor/adaptor proteins. Front Plant Sci 5:1–6

    Google Scholar 

  155. Ventura MT, Casciaro M, Gangemi S, Buquicchio R (2017) Immunosenescence in aging: between immune cells depletion and cytokines up-regulation. Clin Mol Allergy 15:1–8

    Google Scholar 

  156. Verma R, Deshaies RJ (2000) A proteasome howdunit: the case of the missing signal. Cell 101:341–344

    CAS  PubMed  Google Scholar 

  157. Von Zglinicki T, Pilger R, Sitte N (2000) Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts. Free Radic Biol Med 28:64–74

    Google Scholar 

  158. Voronina, E., Seydoux, G., Sassone-Corsi, P., and Nagamori, I. (2011) Cold Spring Harb Perspect Biol. RNA granules in germ cells subject collections

  159. Walther DM, Mann M (2011) Accurate quantification of more than 4000 mouse tissue proteins reveals minimal proteome changes during aging. Mol Cell Proteomics 10:1–7

    Google Scholar 

  160. Williams KW, Liu T, Kong X, Fukuda M, Deng Y, Berglund ED, Deng Z, Gao Y, Liu T, Sohn JW, Jia L, Fujikawa T, Kohno D, Scott MM, Lee S, Lee CE, Sun K, Chang Y, Scherer PE, Elmquist JK (2014) Xbp1s in pomc neurons connects ER stress with energy balance and glucose homeostasis. Cell Metab 20:471–482

    CAS  PubMed Central  PubMed  Google Scholar 

  161. Winckler B, Faundez V, Maday S, Cai Q, Almeida CG, Zhang H (2018) The endolysosomal system and proteostasis: from development to degeneration. J Neurosci 38:9364–9374

    CAS  PubMed Central  PubMed  Google Scholar 

  162. Wrobel L, Topf U, Bragoszewski P, Wiese S, Sztolsztener ME, Oeljeklaus S, Varabyova A, Lirski M, Chroscicki P, Mroczek S, Januszewicz E, Dziembowski A, Koblowska M, Warscheid B, Chacinska A (2015) Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol. Nature 524:485–488

    CAS  PubMed  Google Scholar 

  163. Yamamoto, A., and Lucas, J. (2000) Yamamoto et al. - 2000 - Cell . 101, 57–66

  164. Young, J. C., Hoogenraad, N. J., and Hartl, F. U. (2005) Contents, Ed. Board + Forthc. articles. Trends Biochem. Sci. 30, i

  165. Zhang K, Kaufman RJ (2004) Signaling the unfolded protein response from the endoplasmic reticulum. J Biol Chem 279:25935–25938

    CAS  PubMed  Google Scholar 

  166. Zhang R, Asai M, Mahoney CE, Joachim M, Shen Y, Gunner G, Majzoub JA (2016) Age- and hypertension-associated protein aggregates in mouse heart have similar proteomic profiles. Hypertension 22:733–744

    Google Scholar 

  167. Zheng X, Krakowiak J, Patel N, Beyzavi A, Ezike J, Khalil AS, Pincus D (2016) Dynamic control of HSF1 during heat shock by a chaperone switch and phosphorylation. Elife 5:1–26

    Google Scholar 

  168. Zhu D, Wu X, Zhou J, Li X, Huang X, Li J, Wu J, Bian Q, Wang Y, Tian Y (2020) NuRD mediates mitochondrial stress-induced longevity via chromatin remodeling in response to acetyl-CoA level. Sci Adv 6:1–12

    Google Scholar 

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Acknowledgements

We are thankful to CSIR-CDRI for providing the infrastructure and access to the journals for writing this review.

Funding

AS is a Senior Research Fellow (CSIR) vide reference no EMR/No./31/004(1273)2014-EMR-I. AN acknowledges the funding received from CSIR-CDRI vide project MLP0020 (Neuroscience and Ageing Biology).

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  1. Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow, UP, 226031, India

    Arunabh Sarkar & Aamir Nazir

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  1. Arunabh Sarkar
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AS conducted the research, analyzed data, and wrote the manuscript; AN conceived the study, provided infrastructure, analyzed the data, and edited the manuscript. All authors read the manuscript and agreed its content before the submission.

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Correspondence to Aamir Nazir.

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Sarkar, A., Nazir, A. Carrying Excess Baggage Can Slowdown Life: Protein Clearance Machineries That Go Awry During Aging and the Relevance of Maintaining Them. Mol Neurobiol 59, 821–840 (2022). https://doi.org/10.1007/s12035-021-02640-2

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