Misfolds

Misfolds are polypeptide chains or other biomolecules that fail to attain or maintain their correct native conformation. In proteins, a misfolded state often exposes hydrophobic regions, reducing stability and impairing function. Some misfolds are transient and can be corrected during the folding process, but others persist and may be degraded or become aggregated.

Causes of misfolding include genetic mutations that alter amino acid sequence or folding propensity, errors during translation, post-translational modifications, and environmental or cellular stress such as heat, pH changes, oxidative damage, or overwhelmed chaperone systems. The cellular protein quality control machinery, including molecular chaperones and the ubiquitin-proteasome system, works to refold or remove misfolded proteins. When these systems fail or are saturated, misfolded proteins can accumulate.

Consequences of misfolding range from loss of normal function to toxic gain of function. Aggregation can lead to the formation of soluble oligomers or insoluble fibrils and plaques, which may disrupt membranes, impair proteasome activity, or trigger inflammatory responses. In some cases misfolded proteins can act as seeds that template further misfolding and propagation, as seen in prion-related diseases.

Relevance to health and disease is substantial. Misfolding is implicated in many neurodegenerative disorders, such as Alzheimer’s disease (amyloid-beta and tau), Parkinson’s disease (alpha-synuclein), and Huntington’s disease (huntingtin), as well as systemic amyloidoses and certain cystic and metabolic conditions. Research seeks to map folding pathways, bolster chaperone function, stabilize native conformations, and develop therapies that prevent aggregation or promote clearance of misfolded species.