How do protein misfolding and aggregation cause disease?

Protein misfolding diseases (proteinopathies) result from accumulation of incorrectly folded proteins that form toxic aggregates. In Alzheimer's disease, amyloid-beta peptides aggregate into plaques and tau forms neurofibrillary tangles. Parkinson's involves alpha-synuclein aggregates (Lewy bodies). Prion diseases feature misfolded prion protein that templates misfolding of normal protein. Mechanisms of toxicity include: disruption of cellular proteostasis, membrane damage by oligomers, sequestration of essential proteins, and triggering of apoptosis. Contributing factors include mutations affecting folding, aging-related decline in chaperone function, and oxidative stress. Therapeutic strategies target aggregation prevention, clearance enhancement, and chaperone support.