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Molecular Chaperones Regulating the Dynamics, Composition and Functionality of RNP Granules: Implications for Age-Related Diseases

  • Daniel Mateju
  • Laura Mediani
  • Federica F. Morelli
  • Simon Alberti
  • Serena Carra
Chapter
Part of the Heat Shock Proteins book series (HESP, volume 14)

Abstract

The maturation, storage and degradation of RNAs occur in RNA-protein membrane-less assemblies that have properties of liquid droplets and arise from the surrounding aqueous cytoplasm or nucleoplasm through a process known as liquid-liquid phase separation. In healthy cells, ribonucleoprotein (RNP) granules are highly dynamic compartments. In contrast, in aging cells or due to environmental stresses or genetic mutations, RNP granules, in particular stress granules (SGs), convert into solid, aggregate-like inclusions. The accumulation of these RNA-protein inclusions is linked to an increasing number of age-related neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia. Thus, a detailed understanding of the molecular causes underlying the conversion of liquid-like RNPs into aggregates and the identification of the cellular players that can prevent this conversion may represent a valid approach to combat these diseases.

In this book chapter, we summarize the current knowledge about stress granule formation. We focus on recent findings demonstrating that liquid-like SGs can sequester aggregation-prone misfolded proteins with detrimental consequences for SG dynamics and functionality. We further discuss a specific protein quality control process, referred to as granulostasis, which prevents the accumulation of misfolding-prone proteins in SGs, thereby maintaining the physiological state of SGs and ensuring timely SG disassembly.

Keywords

Membrane-less compartments Molecular chaperones and co-chaperones Neurodegenerative diseases Phase transition Protein aggregation Stress granules 

Abbreviations

AD

Alzheimer’s disease

ALS

amyotrophic lateral sclerosis

BAG

Bcl-2 associated athanogenes

CCT/TRiC

chaperonin-containing t-complex polypeptide 1/TCP-1 ring complex

CHIP

carboxyl terminus of Hsc70-interacting protein

FTD

frontotemporal dementia

FUS

fused in sarcoma

HD

Huntington’s disease

hnRNPA1

heterogeneous nuclear ribonucleoprotein A1

HSP

heat shock proteins

IBM

inclusion body myopathy

IDP

intrinsically disordered protein

IDR

intrinsically disordered region

LC3

microtubule-associated protein 1A/1B-light chain 3

LCS

low-complexity sequences

mTOR

mammalian target of rapamycin

NEFs

nucleotide-exchange factors

PD

Parkinson’s disease

PML

promyelocytic leukemia protein

PQC

protein quality control

RACK1

receptor for activated C kinase 1

RAN

repeat-associated non-ATG

RBP

RNA-binding protein

RNP

ribonucleoprotein particle

SG

stress granule

SOD1

superoxide dismutase 1

SQSTM1

sequestosome 1

TDP-43

TAR DNA-binding protein 43

TIA-1

T-cell intracellular antigen 1

TRAF

TNF receptor associated factor

Notes

Acknowledgments

S.C. is grateful to AriSLA, The Italian Ministry of Foreign Affair and International Cooperation and the Cariplo Foundation for financial support. S.C. and S.A. acknowledge EU Joint Programme – Neurodegenerative Disease Research (JPND) project for financial support. The project is supported through funding organisations under the aegis of JPND (http://www.neurodegenerationresearch.eu/). This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No 643417. S.A. acknowledges funding from the Max Planck Society.

References

  1. Alberti, S., Demand, J., Esser, C., Emmerich, N., Schild, H., & Hohfeld, J. (2002). Ubiquitylation of BAG-1 suggests a novel regulatory mechanism during the sorting of chaperone substrates to the proteasome. The Journal of Biological Chemistry, 277, 45920–45927.CrossRefPubMedCentralPubMedGoogle Scholar
  2. Alberti, S., Halfmann, R., King, O., Kapila, A., & Lindquist, S. (2009). A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell, 137, 146–158.CrossRefPubMedCentralPubMedGoogle Scholar
  3. Alberti, S., Mateju, D., Mediani, L., & Carra, S. (2017). Granulostasis: Protein quality control of RNP granules. Frontiers in Molecular Neuroscience, 10, 84.CrossRefPubMedCentralPubMedGoogle Scholar
  4. Andreasson, C., Fiaux, J., Rampelt, H., Mayer, M. P., & Bukau, B. (2008). Hsp110 is a nucleotide-activated exchange factor for Hsp70. The Journal of Biological Chemistry, 283, 8877–8884.CrossRefPubMedCentralPubMedGoogle Scholar
  5. Arimoto, K., Fukuda, H., Imajoh-Ohmi, S., Saito, H., & Takekawa, M. (2008). Formation of stress granules inhibits apoptosis by suppressing stress-responsive MAPK pathways. Nature Cell Biology, 10, 1324–1332.CrossRefPubMedCentralPubMedGoogle Scholar
  6. Ash, P. E., Bieniek, K. F., Gendron, T. F., Caulfield, T., Lin, W. L., Dejesus-Hernandez, M., van Blitterswijk, M. M., Jansen-West, K., Paul, J. W., 3rd, Rademakers, R., Boylan, K. B., Dickson, D. W., & Petrucelli, L. (2013). Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron, 77, 639–646.CrossRefPubMedCentralPubMedGoogle Scholar
  7. Audas, T. E., Audas, D. E., Jacob, M. D., Ho, J. J., Khacho, M., Wang, M., Perera, J. K., Gardiner, C., Bennett, C. A., Head, T., Kryvenko, O. N., Jorda, M., Daunert, S., Malhotra, A., Trinkle-Mulcahy, L., Gonzalgo, M. L., & Lee, S. (2016). Adaptation to stressors by systemic protein amyloidogenesis. Developmental Cell, 39, 155–168.CrossRefPubMedCentralPubMedGoogle Scholar
  8. Banani, S. F., Lee, H. O., Hyman, A. A., & Rosen, M. K. (2017). Biomolecular condensates: Organizers of cellular biochemistry. Nature Reviews. Molecular Cell Biology, 18, 285–298.CrossRefPubMedCentralPubMedGoogle Scholar
  9. Barker, H. V., Niblock, M., Lee, Y. B., Shaw, C. E., & Gallo, J. M. (2017). RNA misprocessing in C9orf72-linked neurodegeneration. Frontiers in Cellular Neuroscience, 11, 195.CrossRefPubMedCentralPubMedGoogle Scholar
  10. Beckmann, R. P., Mizzen, L. E., & Welch, W. J. (1990). Interaction of Hsp 70 with newly synthesized proteins: Implications for protein folding and assembly. Science, 248, 850–854.CrossRefPubMedCentralPubMedGoogle Scholar
  11. Bjorkoy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Overvatn, A., Stenmark, H., & Johansen, T. (2005). p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. The Journal of Cell Biology, 171, 603–614.CrossRefPubMedCentralPubMedGoogle Scholar
  12. Buchan, J. R. (2014). mRNP granules. Assembly, function, and connections with disease. RNA Biology, 11, 1019–1030.CrossRefPubMedCentralPubMedGoogle Scholar
  13. Buchan, J. R., Kolaitis, R. M., Taylor, J. P., & Parker, R. (2013). Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell, 153, 1461–1474.CrossRefPubMedCentralPubMedGoogle Scholar
  14. Buchner, J. (1999). Hsp90 & Co. – a holding for folding. Trends in Biochemical Sciences, 24, 136–141.CrossRefPubMedCentralPubMedGoogle Scholar
  15. Carra, S., Seguin, S. J., Lambert, H., & Landry, J. (2008). HspB8 chaperone activity toward poly(Q)-containing proteins depends on its association with Bag3, a stimulator of macroautophagy. The Journal of Biological Chemistry, 283, 1437–1444.CrossRefPubMedCentralPubMedGoogle Scholar
  16. Carra, S., Boncoraglio, A., Kanon, B., Brunsting, J. F., Minoia, M., Rana, A., Vos, M. J., Seidel, K., Sibon, O. C., & Kampinga, H. H. (2010). Identification of the Drosophila ortholog of HSPB8: Implication of HSPB8 loss of function in protein folding diseases. The Journal of Biological Chemistry, 285, 37811–37822.CrossRefPubMedCentralPubMedGoogle Scholar
  17. Cherkasov, V., Hofmann, S., Druffel-Augustin, S., Mogk, A., Tyedmers, J., Stoecklin, G., & Bukau, B. (2013). Coordination of translational control and protein homeostasis during severe heat stress. Current Biology, 23, 2452–2462.CrossRefPubMedCentralPubMedGoogle Scholar
  18. Chiti, F., & Dobson, C. M. (2006). Protein misfolding, functional amyloid, and human disease. Annual Review of Biochemistry, 75, 333–366.CrossRefPubMedCentralPubMedGoogle Scholar
  19. Ciryam, P., Kundra, R., Morimoto, R. I., Dobson, C. M., & Vendruscolo, M. (2015). Supersaturation is a major driving force for protein aggregation in neurodegenerative diseases. Trends in Pharmacological Sciences, 36, 72–77.CrossRefPubMedCentralPubMedGoogle Scholar
  20. Demand, J., Alberti, S., Patterson, C., & Hohfeld, J. (2001). Cooperation of a ubiquitin domain protein and an E3 ubiquitin ligase during chaperone/proteasome coupling. Current Biology, 11, 1569–1577.CrossRefPubMedCentralPubMedGoogle Scholar
  21. Ellis, R. J., & Hartl, F. U. (1999). Principles of protein folding in the cellular environment. Current Opinion in Structural Biology, 9, 102–110.CrossRefPubMedCentralPubMedGoogle Scholar
  22. Evgrafov, O. V., Mersiyanova, I., Irobi, J., Van Den Bosch, L., Dierick, I., Leung, C. L., Schagina, O., Verpoorten, N., Van Impe, K., Fedotov, V., Dadali, E., Auer-Grumbach, M., Windpassinger, C., Wagner, K., Mitrovic, Z., Hilton-Jones, D., Talbot, K., Martin, J. J., Vasserman, N., Tverskaya, S., Polyakov, A., Liem, R. K., Gettemans, J., Robberecht, W., De Jonghe, P., & Timmerman, V. (2004). Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nature Genetics, 36, 602–606.CrossRefPubMedCentralPubMedGoogle Scholar
  23. Freibaum, B. D., Lu, Y., Lopez-Gonzalez, R., Kim, N. C., Almeida, S., Lee, K. H., Badders, N., Valentine, M., Miller, B. L., Wong, P. C., Petrucelli, L., Kim, H. J., Gao, F. B., & Taylor, J. P. (2015). GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature, 525, 129–133.CrossRefPubMedCentralPubMedGoogle Scholar
  24. Fuchs, M., Poirier, D. J., Seguin, S. J., Lambert, H., Carra, S., Charette, S. J., & Landry, J. (2009). Identification of the key structural motifs involved in HspB8/HspB6-Bag3 interaction. The Biochemical Journal, 425, 245–255.CrossRefPubMedCentralPubMedGoogle Scholar
  25. Gamerdinger, M., Hajieva, P., Kaya, A. M., Wolfrum, U., Hartl, F. U., & Behl, C. (2009). Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3. The EMBO Journal, 28, 889–901.CrossRefPubMedCentralPubMedGoogle Scholar
  26. Gamerdinger, M., Kaya, A. M., Wolfrum, U., Clement, A. M., & Behl, C. (2011). BAG3 mediates chaperone-based aggresome-targeting and selective autophagy of misfolded proteins. EMBO Reports, 12, 149–156.CrossRefPubMedCentralPubMedGoogle Scholar
  27. Ganassi, M., Mateju, D., Bigi, I., Mediani, L., Poser, I., Lee, H. O., Seguin, S. J., Morelli, F. F., 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. Molecular Cell, 63, 796–810.CrossRefPubMedCentralPubMedGoogle Scholar
  28. Ghaoui, R., Palmio, J., Brewer, J., Lek, M., Needham, M., Evila, A., Hackman, P., Jonson, P. H., Penttila, S., Vihola, A., Huovinen, S., Lindfors, M., Davis, R. L., Waddell, L., Kaur, S., Yiannikas, C., North, K., Clarke, N., MacArthur, D. G., Sue, C. M., & Udd, B. (2016). Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy. Neurology, 86, 391–398.CrossRefPubMedCentralPubMedGoogle Scholar
  29. Gloge, F., Becker, A. H., Kramer, G., & Bukau, B. (2014). Co-translational mechanisms of protein maturation. Current Opinion in Structural Biology, 24, 24–33.CrossRefPubMedCentralPubMedGoogle Scholar
  30. Hartl, F. U., Bracher, A., & Hayer-Hartl, M. (2011). Molecular chaperones in protein folding and proteostasis. Nature, 475, 324–332.CrossRefPubMedCentralPubMedGoogle Scholar
  31. Haslbeck, M., Franzmann, T., Weinfurtner, D., & Buchner, J. (2005). Some like it hot: The structure and function of small heat-shock proteins. Nature Structural & Molecular Biology, 12, 842–846.CrossRefGoogle Scholar
  32. Hipp, M. S., Park, S. H., & Hartl, F. U. (2014). Proteostasis impairment in protein-misfolding and –aggregation diseases. Trends in Cell Biology, 24, 506–514.CrossRefPubMedCentralPubMedGoogle Scholar
  33. Irobi, J., Van Impe, K., Seeman, P., Jordanova, A., Dierick, I., Verpoorten, N., Michalik, A., De Vriendt, E., Jacobs, A., Van Gerwen, V., Vennekens, K., Mazanec, R., Tournev, I., Hilton-Jones, D., Talbot, K., Kremensky, I., Van Den Bosch, L., Robberecht, W., Van Vandekerckhove, J., Van Broeckhoven, C., Gettemans, J., De Jonghe, P., & Timmerman, V. (2004). Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nature Genetics, 36, 597–601.CrossRefPubMedCentralPubMedGoogle Scholar
  34. Jain, S., Wheeler, J. R., Walters, R. W., Agrawal, A., Barsic, A., & Parker, R. (2016). ATPase-modulated stress granules contain a diverse proteome and substructure. Cell, 164, 487–498.CrossRefPubMedCentralPubMedGoogle Scholar
  35. Johnson, J. O., Mandrioli, J., Benatar, M., Abramzon, Y., Van Deerlin, V. M., Trojanowski, J. Q., Gibbs, J. R., Brunetti, M., Gronka, S., Wuu, J., Ding, J., McCluskey, L., Martinez-Lage, M., Falcone, D., Hernandez, D. G., Arepalli, S., Chong, S., Schymick, J. C., Rothstein, J., Landi, F., Wang, Y. D., Calvo, A., Mora, G., Sabatelli, M., Monsurro, M. R., Battistini, S., Salvi, F., Spataro, R., Sola, P., Borghero, G., Galassi, G., Scholz, S. W., Taylor, J. P., Restagno, G., Chio, A., & Traynor, B. J. (2010). Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron, 68, 857–864.CrossRefPubMedCentralPubMedGoogle Scholar
  36. Jovicic, A., Mertens, J., Boeynaems, S., Bogaert, E., Chai, N., Yamada, S. B., Paul, J. W., 3rd, Sun, S., Herdy, J. R., Bieri, G., Kramer, N. J., Gage, F. H., Van Den Bosch, L., Robberecht, W., & Gitler, A. D. (2015). Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nature Neuroscience, 18, 1226–1229.CrossRefPubMedCentralPubMedGoogle Scholar
  37. Kampinga, H. H., & Craig, E. A. (2010). The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nature Reviews Molecular Cell Biology, 11, 579–592.CrossRefPubMedCentralPubMedGoogle Scholar
  38. Kampinga, H. H., Hageman, J., Vos, M. J., Kubota, H., Tanguay, R. M., Bruford, E. A., Cheetham, M. E., Chen, B., & Hightower, L. E. (2009). Guidelines for the nomenclature of the human heat shock proteins. Cell Stress & Chaperones, 14, 105–111.CrossRefGoogle Scholar
  39. Kim, W. J., Back, S. H., Kim, V., Ryu, I., & Jang, S. K. (2005). Sequestration of TRAF2 into stress granules interrupts tumor necrosis factor signaling under stress conditions. Molecular and Cellular Biology, 25, 2450–2462.CrossRefPubMedCentralPubMedGoogle Scholar
  40. King, O. D., Gitler, A. D., & Shorter, J. (2012). The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Research, 1462, 61–80.CrossRefPubMedCentralPubMedGoogle Scholar
  41. Knowles, T. P., Vendruscolo, M., & Dobson, C. M. (2014). The amyloid state and its association with protein misfolding diseases. Nature Reviews Molecular Cell Biology, 15, 384–396.CrossRefPubMedCentralPubMedGoogle Scholar
  42. Kroschwald, S., Maharana, S., Mateju, D., Malinovska, L., Nuske, E., Poser, I., Richter, D., & Alberti, S. (2015). Promiscuous interactions and protein disaggregases determine the material state of stress-inducible RNP granules. eLife, 4, e06807.CrossRefPubMedCentralPubMedGoogle Scholar
  43. Kwiatkowski, T. J., Jr., Bosco, D. A., Leclerc, A. L., Tamrazian, E., Vanderburg, C. R., Russ, C., Davis, A., Gilchrist, J., Kasarskis, E. J., Munsat, T., Valdmanis, P., Rouleau, G. A., Hosler, B. A., Cortelli, P., de Jong, P. J., Yoshinaga, Y., Haines, J. L., Pericak-Vance, M. A., Yan, J., Ticozzi, N., Siddique, T., McKenna-Yasek, D., Sapp, P. C., Horvitz, H. R., Landers, J. E., & Brown, R. H., Jr. (2009). Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science, 323, 1205–1208.CrossRefPubMedCentralPubMedGoogle Scholar
  44. Lagier-Tourenne, C., Polymenidou, M., & Cleveland, D. W. (2010). TDP-43 and FUS/TLS: Emerging roles in RNA processing and neurodegeneration. Human Molecular Genetics, 19, R46–R64.CrossRefPubMedCentralPubMedGoogle Scholar
  45. Laufen, T., Mayer, M. P., Beisel, C., Klostermeier, D., Mogk, A., Reinstein, J., & Bukau, B. (1999). Mechanism of regulation of hsp70 chaperones by DnaJ cochaperones. Proceedings of the National Academy of Sciences of the United States of America, 96, 5452–5457.CrossRefPubMedCentralPubMedGoogle Scholar
  46. Lee, K. H., Zhang, P., Kim, H. J., Mitrea, D. M., Sarkar, M., Freibaum, B. D., Cika, J., Coughlin, M., Messing, J., Molliex, A., Maxwell, B. A., Kim, N. C., Temirov, J., Moore, J., Kolaitis, R. M., Shaw, T. I., Bai, B., Peng, J., Kriwacki, R. W., & Taylor, J. P. (2016). C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell, 167, 774–788. e17.CrossRefPubMedCentralPubMedGoogle Scholar
  47. Li, Y. R., King, O. D., Shorter, J., & Gitler, A. D. (2013). Stress granules as crucibles of ALS pathogenesis. The Journal of Cell Biology, 201, 361–372.CrossRefPubMedCentralPubMedGoogle Scholar
  48. Mackenzie, I. R., Nicholson, A. M., Sarkar, M., Messing, J., Purice, M. D., Pottier, C., Annu, K., Baker, M., Perkerson, R. B., Kurti, A., Matchett, B. J., Mittag, T., Temirov, J., Hsiung, G. R., Krieger, C., Murray, M. E., Kato, M., Fryer, J. D., Petrucelli, L., Zinman, L., Weintraub, S., Mesulam, M., Keith, J., Zivkovic, S. A., Hirsch-Reinshagen, V., Roos, R. P., Zuchner, S., Graff-Radford, N. R., Petersen, R. C., Caselli, R. J., Wszolek, Z. K., Finger, E., Lippa, C., Lacomis, D., Stewart, H., Dickson, D. W., Kim, H. J., Rogaeva, E., Bigio, E., Boylan, K. B., Taylor, J. P., & Rademakers, R. (2017). TIA1 mutations in amyotrophic lateral sclerosis and frontotemporal dementia promote phase separation and alter stress granule dynamics. Neuron, 95, 808–816. e9.CrossRefPubMedCentralPubMedGoogle Scholar
  49. March, Z. M., King, O. D., & Shorter, J. (2016). Prion-like domains as epigenetic regulators, scaffolds for subcellular organization, and drivers of neurodegenerative disease. Brain Research, 1647, 9–18.CrossRefPubMedCentralPubMedGoogle Scholar
  50. Mateju, D., Franzmann, T. M., Patel, A., Kopach, A., Boczek, E. E., Maharana, S., Lee, H. O., Carra, S., Hyman, A. A., & Alberti, S. (2017). An aberrant phase transition of stress granules triggered by misfolded protein and prevented by chaperone function. The EMBO Journal, 36, 1669–1687.CrossRefPubMedCentralPubMedGoogle Scholar
  51. Mayer, M. P., & Bukau, B. (2005). Hsp70 chaperones: Cellular functions and molecular mechanism. Cellular and Molecular Life Sciences, 62, 670–684.CrossRefPubMedCentralPubMedGoogle Scholar
  52. Mayer, M. P., Schroder, H., Rudiger, S., Paal, K., Laufen, T., & Bukau, B. (2000). Multistep mechanism of substrate binding determines chaperone activity of Hsp70. Nature Structural Biology, 7, 586–593.CrossRefPubMedCentralPubMedGoogle Scholar
  53. Mazroui, R., Di Marco, S., Kaufman, R. J., & Gallouzi, I. E. (2007). Inhibition of the ubiquitin-proteasome system induces stress granule formation. Molecular Biology of the Cell, 18, 2603–2618.CrossRefPubMedCentralPubMedGoogle Scholar
  54. Minoia, M., Boncoraglio, A., Vinet, J., Morelli, F. F., Brunsting, J. F., Poletti, A., Krom, S., Reits, E., Kampinga, H. H., & Carra, S. (2014). BAG3 induces the sequestration of proteasomal clients into cytoplasmic puncta: Implications for a proteasome-to-autophagy switch. Autophagy, 10, 1603–1621.CrossRefPubMedCentralPubMedGoogle Scholar
  55. Mizuno, Y., Amari, M., Takatama, M., Aizawa, H., Mihara, B., & Okamoto, K. (2006). Immunoreactivities of p62, an ubiqutin-binding protein, in the spinal anterior horn cells of patients with amyotrophic lateral sclerosis. Journal of the Neurological Sciences, 249, 13–18.CrossRefPubMedCentralPubMedGoogle Scholar
  56. Molliex, A., Temirov, J., Lee, J., Coughlin, M., Kanagaraj, A. P., Kim, H. J., Mittag, T., & Taylor, J. P. (2015). Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell, 163, 123–133.CrossRefPubMedCentralPubMedGoogle Scholar
  57. Morgan, S., & Orrell, R. W. (2016). Pathogenesis of amyotrophic lateral sclerosis. British Medical Bulletin, 119, 87–98.CrossRefPubMedCentralPubMedGoogle Scholar
  58. Mori, K., Weng, S. M., Arzberger, T., May, S., Rentzsch, K., Kremmer, E., Schmid, B., Kretzschmar, H. A., Cruts, M., Van Broeckhoven, C., Haass, C., & Edbauer, D. (2013). The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science, 339, 1335–1338.CrossRefPubMedCentralGoogle Scholar
  59. Morimoto, R. I., & Cuervo, A. M. (2014). Proteostasis and the aging proteome in health and disease. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 69 (Suppl 1), S33–S38.CrossRefPubMedCentralPubMedGoogle Scholar
  60. Murakami, T., Qamar, S., Lin, J. Q., Schierle, G. S., Rees, E., Miyashita, A., Costa, A. R., Dodd, R. B., Chan, F. T., Michel, C. H., Kronenberg-Versteeg, D., Li, Y., Yang, S. P., Wakutani, Y., Meadows, W., Ferry, R. R., Dong, L., Tartaglia, G. G., Favrin, G., Lin, W. L., Dickson, D. W., Zhen, M., Ron, D., Schmitt-Ulms, G., Fraser, P. E., Shneider, N. A., Holt, C., Vendruscolo, M., Kaminski, C. F., & St George-Hyslop, P. (2015). ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function. Neuron, 88, 678–690.CrossRefPubMedCentralPubMedGoogle Scholar
  61. Patel, A., Lee, H. O., Jawerth, L., Maharana, S., Jahnel, M., Hein, M. Y., Stoynov, S., Mahamid, J., Saha, S., Franzmann, T. M., Pozniakovski, A., Poser, I., Maghelli, N., Royer, L. A., Weigert, M., Myers, E. W., Grill, S., Drechsel, D., Hyman, A. A., & Alberti, S. (2015). A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell, 162, 1066–1077.CrossRefPubMedCentralPubMedGoogle Scholar
  62. Protter, D. S., & Parker, R. (2016). Principles and properties of stress granules. Trends in Cell Biology, 26, 668–679.CrossRefPubMedCentralPubMedGoogle Scholar
  63. Prudlo, J., Konig, J., Schuster, C., Kasper, E., Buttner, A., Teipel, S., & Neumann, M. (2016). TDP-43 pathology and cognition in ALS: A prospective clinicopathologic correlation study. Neurology, 87, 1019–1023.CrossRefPubMedCentralPubMedGoogle Scholar
  64. Qian, S. B., McDonough, H., Boellmann, F., Cyr, D. M., & Patterson, C. (2006). CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70. Nature, 440, 551–555.CrossRefPubMedCentralPubMedGoogle Scholar
  65. Rauch, J. N., & Gestwicki, J. E. (2014). Binding of human nucleotide exchange factors to heat shock protein 70 (Hsp70) generates functionally distinct complexes in vitro. The Journal of Biological Chemistry, 289, 1402–1414.CrossRefPubMedCentralPubMedGoogle Scholar
  66. Rauch, J. N., Tse, E., Freilich, R., Mok, S. A., Makley, L. N., Southworth, D. R., & Gestwicki, J. E. (2017). BAG3 is a modular, scaffolding protein that physically links heat shock protein 70 (Hsp70) to the small heat shock proteins. Journal of Molecular Biology, 429, 128–141.CrossRefPubMedCentralPubMedGoogle Scholar
  67. Rea, S. L., Majcher, V., Searle, M. S., & Layfield, R. (2014). SQSTM1 mutations – bridging Paget disease of bone and ALS/FTLD. Experimental Cell Research, 325, 27–37.CrossRefPubMedCentralPubMedGoogle Scholar
  68. Rosen, D. R., Siddique, T., Patterson, D., Figlewicz, D. A., Sapp, P., Hentati, A., Donaldson, D., Goto, J., O’Regan, J. P., Deng, H. X., et al. (1993). Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature, 362, 59–62.CrossRefPubMedCentralPubMedGoogle Scholar
  69. Ruegsegger, C., & Saxena, S. (2016). Proteostasis impairment in ALS. Brain Research, 1648, 571–579.CrossRefPubMedCentralPubMedGoogle Scholar
  70. Schmid, D., Baici, A., Gehring, H., & Christen, P. (1994). Kinetics of molecular chaperone action. Science, 263, 971–973.CrossRefPubMedCentralPubMedGoogle Scholar
  71. Schubert, U., Anton, L. C., Gibbs, J., Norbury, C. C., Yewdell, J. W., & Bennink, J. R. (2000). Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature, 404, 770–774.CrossRefPubMedCentralPubMedGoogle Scholar
  72. Scotter, E. L., Chen, H. J., & Shaw, C. E. (2015). TDP-43 proteinopathy and ALS: Insights into disease mechanisms and therapeutic targets. Neurotherapeutics, 12, 352–363.CrossRefPubMedCentralPubMedGoogle Scholar
  73. Seguin, S. J., Morelli, F. F., Vinet, J., Amore, D., De Biasi, S., Poletti, A., Rubinsztein, D. C., & Carra, S. (2014). Inhibition of autophagy, lysosome and VCP function impairs stress granule assembly. Cell Death and Differentiation, 21, 1838–1851.CrossRefPubMedCentralPubMedGoogle Scholar
  74. Selcen, D., Muntoni, F., Burton, B. K., Pegoraro, E., Sewry, C., Bite, A. V., & Engel, A. G. (2009). Mutation in BAG3 causes severe dominant childhood muscular dystrophy. Annals of Neurology, 65, 83–89.CrossRefPubMedCentralPubMedGoogle Scholar
  75. Shemetov, A. A., & Gusev, N. B. (2011). Biochemical characterization of small heat shock protein HspB8 (Hsp22)-Bag3 interaction. Archives of Biochemistry and Biophysics, 513, 1–9.CrossRefPubMedCentralPubMedGoogle Scholar
  76. Sreedharan, J., Blair, I. P., Tripathi, V. B., Hu, X., Vance, C., Rogelj, B., Ackerley, S., Durnall, J. C., Williams, K. L., Buratti, E., Baralle, F., de Belleroche, J., Mitchell, J. D., Leigh, P. N., Al-Chalabi, A., Miller, C. C., Nicholson, G., & Shaw, C. E. (2008). TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science, 319, 1668–1672.CrossRefPubMedCentralPubMedGoogle Scholar
  77. Stojanovski, D., Bohnert, M., Pfanner, N., & van der Laan, M. (2012). Mechanisms of protein sorting in mitochondria. Cold Spring Harbor Perspective Biology, 4, a011320.CrossRefGoogle Scholar
  78. Takahara, T., & Maeda, T. (2012). Transient sequestration of TORC1 into stress granules during heat stress. Molecular Cell, 47, 242–252.CrossRefPubMedCentralPubMedGoogle Scholar
  79. Takayama, S., & Reed, J. C. (2001). Molecular chaperone targeting and regulation by BAG family proteins. Nature Cell Biology, 3, E237–E241.CrossRefPubMedCentralPubMedGoogle Scholar
  80. Taylor, A. A., Fournier, C., Polak, M., Wang, L., Zach, N., Keymer, M., Glass, J. D., & Ennist, D. L. (2016a). Predicting disease progression in amyotrophic lateral sclerosis. Annals of Clinical Translational Neurology, 3, 866–875.CrossRefPubMedCentralPubMedGoogle Scholar
  81. Taylor, J. P., Brown, R. H., Jr., & Cleveland, D. W. (2016b). Decoding ALS: From genes to mechanism. Nature, 539, 197–206.CrossRefPubMedCentralPubMedGoogle Scholar
  82. Teyssou, E., Takeda, T., Lebon, V., Boillee, S., Doukoure, B., Bataillon, G., Sazdovitch, V., Cazeneuve, C., Meininger, V., LeGuern, E., Salachas, F., Seilhean, D., & Millecamps, S. (2013). Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: Genetics and neuropathology. Acta Neuropathologica, 125, 511–522.CrossRefPubMedCentralPubMedGoogle Scholar
  83. Vance, C., Rogelj, B., Hortobagyi, T., De Vos, K. J., Nishimura, A. L., Sreedharan, J., Hu, X., Smith, B., Ruddy, D., Wright, P., Ganesalingam, J., Williams, K. L., Tripathi, V., Al-Saraj, S., Al-Chalabi, A., Leigh, P. N., Blair, I. P., Nicholson, G., de Belleroche, J., Gallo, J. M., Miller, C. C., & Shaw, C. E. (2009). Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science, 323, 1208–1211.CrossRefPubMedCentralPubMedGoogle Scholar
  84. Verma, R., Oania, R. S., Kolawa, N. J., & Deshaies, R. J. (2013). Cdc48/p97 promotes degradation of aberrant nascent polypeptides bound to the ribosome. eLife, 2, e00308.CrossRefPubMedCentralPubMedGoogle Scholar
  85. Walters, R. W., & Parker, R. (2015). Coupling of ribostasis and proteostasis: Hsp70 proteins in mRNA metabolism. Trends in Biochemical Sciences, 40, 552–559.CrossRefPubMedCentralPubMedGoogle Scholar
  86. Wang, F., Durfee, L. A., & Huibregtse, J. M. (2013). A cotranslational ubiquitination pathway for quality control of misfolded proteins. Molecular Cell, 50, 368–378.CrossRefPubMedCentralPubMedGoogle Scholar
  87. Xu, Z., Page, R. C., Gomes, M. M., Kohli, E., Nix, J. C., Herr, A. B., Patterson, C., & Misra, S. (2008). Structural basis of nucleotide exchange and client binding by the Hsp70 cochaperone Bag2. Nature Structural & Molecular Biology, 15, 1309–1317.CrossRefGoogle Scholar
  88. Yewdell, J. W. (2011). DRiPs solidify: Progress in understanding endogenous MHC class I antigen processing. Trends in Immunology, 32, 548–558.CrossRefPubMedCentralPubMedGoogle Scholar
  89. Zhang, K., Donnelly, C. J., Haeusler, A. R., Grima, J. C., Machamer, J. B., Steinwald, P., Daley, E. L., Miller, S. J., Cunningham, K. M., Vidensky, S., Gupta, S., Thomas, M. A., Hong, I., Chiu, S. L., Huganir, R. L., Ostrow, L. W., Matunis, M. J., Wang, J., Sattler, R., Lloyd, T. E., & Rothstein, J. D. (2015). The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature, 525, 56–61.CrossRefPubMedCentralPubMedGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
  2. 2.Department of Biomedical, Metabolic and Neural Sciences, Center for Neuroscience and NeurotechnologyUniversity of Modena and Reggio EmiliaModenaItaly

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