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Protein aggregation in neurodegenerative disease: the nucleolar connection

Institute of Biosciences and Medical Technology, University of Tampere, FI-33014, Finland

Special Issues: Molecular Mechanisms of Neurodegenerative Diseases

Protein- and sometimes RNA-containing aggregates are a hallmark of many age-related neurodegenerative diseases. Aggregate depositions can be cytoplasmic, nuclear and even extracellular. This article focuses on nuclear aggregation and the potential role of a specific compartment—the nucleolus, in the process. The nucleolus is a formation site of nucleolar aggresomes—protein and RNA aggregates formed in vitro by hampered proteasome function. Whether the nucleolar aggresomes are connected to nuclear aggregation involved in certain neurodegenerative diseases is an intriguing question for future studies. In addition, recent evidence connecting aggregation and aggregate sorting in the cytoplasm to membrane-enveloped organelles, namely ER and mitochondria, raises the question whether nuclear aggregation and aggregate positioning is controlled by different mechanisms or by the only membrane available—the nuclear membrane.
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References

1. Labbadia J, Morimoto RI (2015) The Biology of Proteostasis in Aging and Disease. Annu Rev Biochem 84: 435-464.

2. Gallagher PS, Oeser ML, Abraham AC, et al. (2014) Cellular maintenance of nuclear protein homeostasis. Cell Mol Life Sci 71: 1865-1879.    

3. Hart FU, Bracher A, Hayer-Hartl M (2011) Molecular chaperones in protein folding and proteostasis. Nature 475: 324-332.    

4. Lamark T, Johansen T (2012) Aggrephagy: selective disposal of protein aggregates by macroautophagy. Int J Cell Biol 2012: 736905.

5. Shibata Y, Morimoto RI (2014) How the nucleus copes with proteotoxic stress. CurrBiol 24: R463-474.

6. Gray DA, Woulfe J (2013) Structural disorder and the loss of RNA homeostasis in aging and neurodegenerative disease. Front Genet 4: 149.

7. Arslan MA, Chikina M, Csermely P, et al. (2012) Misfolded proteins inhibit proliferation and promote stress-induced death in SV40-transformed mammalian cells. FASEB J 26: 766-777.    

8. Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292: 1552-1555.    

9. Holmberg CI, Staniszewski KE, Mensah KN, et al. (2004) Inefficient degradation of truncated polyglutamine proteins by the proteasome. EMBO J 23: 4307-4318.    

10. Bennett EJ, Bence NF, Jayakumar R, et al. (2005) Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation. Mol Cell 17: 351-365.    

11. Hipp MS, Patel CN, Bersuker K, et al. (2012) Indirect inhibition of 26S proteasome activity in a cellular model of Huntington’s disease. J Cell Biol 196: 573-857.    

12. Hipp MS, Park SH, Hartl FU (2014) Proteostasis impairment in protein-misfolding and -aggregation diseases. Trends Cell Biol 24: 506-514.    

13. Takalo M, Salminen A, Soininen H, et al. (2013) Protein aggregation and degradation mechanisms in neurodegenerative diseases. Am J Neurodegener Dis 2: 1-14.

14. Latonen L (2011) Nucleolar aggresomes as counterparts of cytoplasmic aggresomes in proteotoxic stress. Bioessays 33: 386-395.    

15. Woulfe J (2008) Nuclear bodies in neurodegenerative disease. Biochim BiophysActa 1783: 2195-2206.

16. Ramaswami M, Taylor JP, Parker R (2013) RNA-Protein Granules in Degenerative Disorders. Cell 154: 727-736.    

17. Miller SB, Ho CT, Winkler J, et al. (2015) Compartment-specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition. EMBO J 34: 778-797.    

18. Dundr M (2012) Nuclear bodies: multifunctional companions of the genome. Curr Opin Cell Biol 24: 415-422.    

19. Kaganovich D, Kopito R, Frydman J (2008) Misfolded proteins partition between two distinct quality control compartments. Nature 454: 1088-1095.    

20. Park SH, Kukushkin Y, Gupta R, et al. (2013) PolyQ proteins interfere with nuclear degradation of cytosolic proteins by sequestering the Sis1p chaperone. Cell 154: 134-145.    

21. Lu M, Williamson N, Boschetti C, et al. (2015) Expression-level dependent perturbation of cell proteostasis and nuclear morphology by aggregation-prone polyglutamine proteins. Biotechnol Bioeng. doi: 10.1002/bit.25606.

22. Caron NS, Hung CL, Atwal RS, et al. (2014) Live cell imaging and biophotonic methods reveal two types of mutant huntingin inclusions. Hum Mol Genet 23: 2324-2338.    

23. Chapple JP, Bros-Facer V, Butler R, et al. (2008) Focal distortion of the nuclear envelope by huntingtin aggregates revealed by lamin immunostaining. Neurosci Lett 447: 172-174.    

24. Mapelli L, Canale C, Pesci D, et al. (2012) Toxic effects of expanded ataxin-1 involve mechanical instability of the nuclear membrane. Biochim Biophys Acta 1822: 906-917.    

25. Lindström MS, Latonen L (2013) The nucleolus as a stress respose organelle. In: Proteins of the Nucleolus. Regulation, Translocation and Biomedical Functions. Springer, 251-273.

26. Andersen JS, Lam YW, Leung AK, et al. (2005) Nucleolar proteome dynamics. Nature 433: 77-83.    

27. Latonen L, Moore HM, Bai B, et al. (2011) Proteasome inhibitors induce nucleolar aggregation of proteasome target proteins and polyadenylated RNA by altering ubiquitin availability. Oncogene 30: 790-805.    

28. Krüger T, Scheer U (2010) p53 localizes to intranucleolar regions distinct from the ribosome production compartments. J Cell Sci 123: 1203-1208.    

29. Vilotti S, Biagioli M, Foti R, et al. (2012) The PML nuclear bodies-associated protein TTRAP regulates ribosome biogenesis in nucleolar cavities upon proteasome inhibition. Cell Death Differ 19: 488-500.    

30. Ehm P, Nalaskowski MM, Wundenberg T, et al. (2015) The tumor suppressor SHIP1 colocalizes in nucleolar cavities with p53 and components of PML nuclear bodies. Nucleus 6: 154-164.    

31. Nollen EA, Salomons FA, Brunsting JF, et al. (2001) Dynamic changes in the localization of thermally unfolded nuclear proteins associated with chaperone-dependent protection. Proc Natl AcadSci USA 98: 12038-12043.    

32. Forsberg K, Andersen PM, Marklund SL, et al. (2011) Glial nuclear aggregates of superoxide dismutase-1 are regularly present in patients with amyotrophic lateral sclerosis. Acta Neuropathol 121: 623-634.    

33. Li M, Nakagomi Y, Kobayashi Y, et al. (1998) Nonneural nuclear inclusions of androgen receptor protein in spinal and bulbar muscular atrophy. Am J Pathol 153: 695-701.

34. Hetman M, Pietrzak M (2012) Emerging roles of the neuronal nucleolus. Trends Neurosci 35: 305-314.    

35. Parlato R, Kreiner G (2013) Nucleolar activity in neurodegenerative diseases: a missing piece of the puzzle? J Mol Med (Berl) 91: 541-547.    

36. Stavreva DA, Kawasaki M, Dundr M, et al. (2006) Potential roles for ubiquitin and the proteasome during ribosome biogenesis. Mol Cell Biol 26: 5131-5145    

37. Nyström T, Liu B (2014) The mystery of aging and rejuvenation—a budding topic. Curr Opin Microbiol 18: 61-67.    

38. Song J, Yang Q, Yang J, et al. (2014) Essential genetic interactors of SIR2 required for spatial sequestration and asymmetrical inheritance of protein aggregates. PLoS Genet 10: e1004539.    

39. Liu B, Larsson L, Caballero A, et al. (2010) The polarisome is required for segregation and retrograde transport of protein aggregates. Cell 140: 257-267.    

40. Zhou C, Slaughter BD, Unruh JR, et al. (2014) Organelle-based aggregation and retention of damaged proteins in asymmetrically dividing cells. Cell 159: 530-542.    

41. Katajisto P, Döhla J, Chaffer CL, et al. (2015) Stem cells. Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness. Science 348: 340-343.

42. Mogk A, Bukau B (2014) Mitochondria tether protein trash to rejuvenate cellular environments. Cell 159: 471-472.    

Copyright Info: © 2015, Leena Latonen, licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

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