proteinaggregation

Protein aggregation refers to the process by which soluble proteins misfold and assemble into higher-order structures, including oligomers, protofibrils, and amyloid fibrils. Aggregation can be triggered by mutations, changes in pH, temperature, ionic strength, or other cellular stress that destabilizes native conformations. Aggregates can form inside cells or in the extracellular space and may disrupt cellular function by sequestering essential proteins, disrupting membranes, perturbing proteostasis, or provoking inflammatory responses. Although many aggregates are associated with disease, not all protein assemblies are pathogenic; some serve physiological roles, such as functional amyloids involved in pigment deposition, hormone storage, or structural scaffolding in certain organisms.

Pathological aggregation is linked to several diseases, most notably neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and prion diseases. In these conditions, misfolded proteins—beta-amyloid and tau in Alzheimer's, alpha-synuclein in Parkinson's, mutant huntingtin in Huntington's, and prion protein in prion diseases—aggregate into oligomers and fibrils that disrupt tissue homeostasis. Toxic species are often soluble oligomers that impair membranes, synaptic function, and cellular energy; mature deposits can also cause tissue damage.

Cells employ proteostasis networks to prevent aggregation, including molecular chaperones, the ubiquitin-proteasome system, and autophagy. When these systems fail, aggregation can accumulate. Research aims to understand aggregation mechanisms and to develop therapies that reduce formation or promote clearance, such as stabilizers of native folding, aggregation inhibitors, and antibodies targeting aggregated species.