Protein aggregation

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Protein aggregation is a biological phenomenon in which mis-folded proteins aggregate (i.e., accumulate and clump together) either intra- or extracellularly.[1][2] These protein aggregates are often toxic; protein aggregates have been implicated in a wide variety of disease known as amyloidoses, including ALS, Alzheimer's, Parkinson's and prion disease.[3][4]


After synthesis, proteins typically fold into a particular three-dimensional conformation: their native state. Only in their native state are they functional. This folding process is driven by the hydrophobic effect: a tendency for hydrophobic (i.e., “oil-ly”) portions of the protein to shield itself from the hydrophilic interior of the cell by burying into the interior of the protein. Thus, the exterior of a protein is typically hydrophilic, whereas the interior is typically hydrophobic.

However, newly synthesized proteins may not fold correctly, or properly folded proteins can spontaneously misfold. In these cases, if the cell does not assist the protein in re-folding, or degrade the unfolded protein, the unfolded protein may aggregate.[5][6] In this process, exposed hydrophobic portions of the unfolded protein may interact with the exposed hydrophobic patches of other unfolded proteins, spontaneously leading to protein aggregation.


Protein aggregation can occur due to a variety of causes. Individuals may have mutations that encode for proteins that are particularly sensitive to misfolding and aggregation. Alternatively, disruption of the pathways to refold proteins (chaperones) or to degrade misfolded proteins (the ubiquitin-proteasome pathway) may lead to protein aggregation. As many of the diseases associated with protein aggregation increase in frequency with age, it seems that cells lose the ability to clear misfolded proteins and aggregates over time. Several new studies suggest that protein aggregation is a second line of the cellular reaction to an imbalanced protein homeostasis rather than a harmful, random process.[7] A groundbreaking study[8] showed that sequestration of misfolded, aggregation-prone proteins into inclusion sites is an active organized cellular process, that depends on quality control components, such as HSPs and co-chaperones. Moreover, it was shown that eukaryotic cells have the ability to sort misfolded proteins in to two quality control compartments: 1. The JUNQ (JUxta Nuclear Quality control compartment). 2. The IPOD (Insoluble Protein Deposit). The partition into two quality control compartments is due to the different handling and processing of the different kinds of misfolded aggregative proteins: The IPOD serves as a sequestration site for non-ubiquitinated terminally aggregated proteins, such as the huntingtin protein. Under stress conditions, such as heat, when the cellular quality control machinery is saturated, ubiquitinated proteins are sorted to the JUNQ compartment, where they are eventually degraded. Thus, aggregation is a regulated, controlled process.

Protein aggregation and Ageing[edit]

The hypothesis that protein aggregation is a causative process in ageing is testable now since some models of delayed ageing are in hand. If the development of protein aggregates was an ageing independent process, slowing down aging will show no effect on the rate of proteotoxicity over time. However, if ageing is associated with decline in the activity of protective mechanisms against proteotoxicity, the slow aging models would show reduced aggregation and proteotoxicity. To address this problem several toxicity assays have been done in C. elegans. These studies indicated that reducing the activity of insulin/IGF signaling (IIS), a prominent aging regulatory pathway protects from neurodegeneration-linked toxic protein aggregation. The validity of this approach has been tested and confirmed in mammals as reducing the activity of the IGF-1 signaling pathway protected Alzheimer's model mice from the behavioral and biochemical impairments associated with the disease.[9]


Although it has been thought that the mature protein aggregates themselves are toxic, recent evidence suggests that it is in fact that immature protein aggregates are most toxic.[10][11] The hydrophobic patches of these aggregates can interact with other components of the cell and damage them. One hypothesis about how protein aggregates damage cells is through disruption of cell membranes. It is known that protein aggregates in vitro can destabilize artificial phospholipid bilayers, leading to permeabilization of the membrane.

See also[edit]

External links[edit]


  1. ^ Aguzzi, A.; O'Connor, T. (March 2010). "Protein aggregation diseases: pathogenicity and therapeutic perspectives.". Nature Reviews Drug Discovery 9 (3): 237–48. doi:10.1038/nrd3050. PMID 20190788. 
  2. ^ Stefani, M.; Dobson, CM. (November 2003). "Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution.". J Mol Med (Berl) 81 (11): 678–99. doi:10.1007/s00109-003-0464-5. PMID 12942175. 
  3. ^ De Felice, FG.; Vieira, MN.; Meirelles, MN.; Morozova-Roche, LA.; Dobson, CM.; Ferreira, ST. (July 2004). "Formation of amyloid aggregates from human lysozyme and its disease-associated variants using hydrostatic pressure.". FASEB J 18 (10): 1099–101. doi:10.1096/fj.03-1072fje. PMID 15155566. 
  4. ^ Tanzi, RE.; Bertram, L. (February 2005). "Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective.". Cell 120 (4): 545–55. doi:10.1016/j.cell.2005.02.008. PMID 15734686. 
  5. ^ Gething, MJ.; Sambrook, J. (January 1992). "Protein folding in the cell". Nature 355 (6355): 33–45. doi:10.1038/355033a0. PMID 1731198. 
  6. ^ Roberts, CJ. (December 2007). "Non-native protein aggregation kinetics". Biotechnol Bioeng 98 (5): 927–38. doi:10.1002/bit.21627. PMID 17705294. 
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  9. ^ "The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditiselegans". PNAS. 2002. doi:10.1073/pnas.152161099. 
  10. ^ Zhu, YJ.; Lin, H.; Lal, R. (June 2000). "Fresh and nonfibrillar amyloid beta protein(1-40) induces rapid cellular degeneration in aged human fibroblasts: evidence for AbetaP-channel-mediated cellular toxicity". FASEB J 14 (9): 1244–54. PMID 10834946. 
  11. ^ Nilsberth, C.; Westlind-Danielsson, A.; Eckman, CB.; Condron, MM.; Axelman, K.; Forsell, C.; Stenh, C.; Luthman, J.; Teplow, DB.; et al. (September 2001). "The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation". Nat Neurosci 4 (9): 887–93. doi:10.1038/nn0901-887. PMID 11528419.