Protein Aggregation
The clumping together of misfolded proteins into insoluble aggregates. Protein aggregation is a hallmark of neurodegenerative diseases (amyloid plaques in Alzheimer's, Lewy bodies in Parkinson's) and a quality concern in peptide manufacturing where aggregated peptides may be immunogenic or inactive.
Technical Context
Aggregation pathways: non-covalent (hydrophobic interactions between exposed surfaces of partially unfolded proteins → soluble oligomers → insoluble amorphous aggregates or ordered amyloid fibrils) and covalent (disulphide bond-mediated crosslinking between oxidised cysteine residues → non-reducible aggregates). In neurodegenerative diseases: amyloid-β aggregates (Alzheimer's), α-synuclein aggregates/Lewy bodies (Parkinson's), tau tangles (Alzheimer's and other tauopathies), huntingtin polyQ aggregates (Huntington's), TDP-43 aggregates (ALS/FTD), and prion protein aggregates (prion diseases). In pharmaceutical manufacturing: peptide aggregation is a major quality concern because aggregated peptides may be: biologically inactive (reduced potency), immunogenic (aggregates can break immune tolerance, triggering anti-drug antibody formation), and difficult to detect by standard HPLC (requiring size-exclusion chromatography, dynamic light scattering, or analytical ultracentrifugation). Formulation strategies to prevent aggregation: optimising pH, adding surfactants (polysorbate 80), controlling temperature, and minimising agitation during processing and storage.