Protein aggregation

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 Alzheimer’s, Parkinson’s and prion disease. ^[3][4]

Introduction

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.

Causes

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 that arise due to protein aggregation increase in frequency with age, it seems that protein aggregates accumulate over time, and/or cells lose the ability to clear misfolded proteins and aggregates over time.

Toxicity

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^[7] .^[8] 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 permabilization of the membrane.

See also

• Amyloid
• Proteopathy
• Amyloidosis

References

1. ^ Aguzzi, A.; O'Connor, T. (Mar 2010). "Protein aggregation diseases: pathogenicity and therapeutic perspectives.". Nat Rev Drug Discov 9 (3): 237–48. doi:10.1038/nrd3050. PMID 20190788. 
2. ^ Stefani, M.; Dobson, CM. (Nov 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. (Jul 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. (Feb 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. (Jan 1992). "Protein folding in the cell.". Nature 355 (6355): 33–45. doi:10.1038/355033a0. PMID 1731198. 
6. ^ Roberts, CJ. (Dec 2007). "Non-native protein aggregation kinetics.". Biotechnol Bioeng 98 (5): 927–38. doi:10.1002/bit.21627. PMID 17705294. 
7. ^ Zhu, YJ.; Lin, H.; Lal, R. (Jun 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. 
8. ^ Nilsberth, C.; Westlind-Danielsson, A.; Eckman, CB.; Condron, MM.; Axelman, K.; Forsell, C.; Stenh, C.; Luthman, J. et al (Sep 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.