protein aggregation

Aggregation is a complex multi-step process of protein conformational change and accretion. The early species in this process might be most toxic, perhaps through the exposure of buried moieties such as main chain NH and CO groups that could serve as hydrogen bond donors or acceptors in abnormal interactions with other cellular proteins.

Pathology

 Abnormal or misfolded proteins may deposit in tissues and interfere with normal functions. The deposits can be intracellular, extracellular, or both, and there is accumulating evidence that the aggregates may either directly or indirectly cause the pathologic changes. Certain forms of amyloidosis fall in this category of diseases. These disorders are sometimes called proteinopathies or protein-aggregation diseases.

 Abnormal protein aggregation is a common characteristic of many neurodegenerative diseases of the brain. Filamentous deposits made of the microtubule-associated protein tau constitute a major defining characteristic of several neurodegenerative diseases known as tauopathies.

 In tauopathies, tau aggregation (TAU) is directly associated with development of neurodegeneration and neuronal death.

Brain

Aggregation of proteins in the brain is a common theme in a diverse group of disorders.

The aggregation of tau (MAPT) in Alzheimer disease and various tauopathies is but one example of abnormal protein-protein interactions that result in the intracellular accumulation of filamentous proteins.

Abnormal protein aggregation is observed in a large number of neurodegenerative disorders
 Alzheimer disease (AD) is characterized by the extracellular accumulation of Aβ fibrils in the form of amyloid plaques;
 Lewy body disorders contain intracytoplasmic filamentous aggregates of α-synuclein;
 trinucleotide repeat disorders have intranuclear inclusions composed of fibrous polyglutamines;
 spongiform encephalopathies demonstrate aggregates of proteinase-resistant prion protein.

See also

 protein aggregates

• intraneuronal protein aggregates (neurofibrillary tangles or NFTs)
• extraneuronal protein aggregates

References

 Slow EJ, Graham RK, Hayden MR. To be or not to be toxic: aggregations in Huntington and Alzheimer disease. Trends Genet. 2006 Aug;22(8):408-11. PMID: 16806565

 Ross CA, Poirier MA. Opinion: What is the role of protein aggregation in neurodegeneration? Nat Rev Mol Cell Biol. 2005 Nov;6(11):891-8. PMID: 16167052

 Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nat Med. 2004 Jul;10 Suppl:S10-7. PMID: 15272267

 Yancopoulou D, Spillantini MG. Tau protein in familial and sporadic diseases. Neuromolecular Med. 2003;4(1-2):37-48. Review. PMID: 14528051

 Trojanowski JQ, Mattson MP. Overview of protein aggregation in single, double, and triple neurodegenerative brain amyloidoses. Neuromolecular Med. 2003;4(1-2):1-6. PMID: 14528048

 Caughey B, Lansbury PT. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci. 2003;26:267-98. PMID: 12704221

 Horwich A: Protein aggregation in disease: a role for folding intermediates forming specific multimeric interactions. J Clin Invest 110:1221, 2002.