Characteristics of the main disease-associated proteins discussed in this perspective.

Protein	Disease	Isoforms and post-translational modifications	Aggregation behaviour in vitro	Ref.
Amyloid-β	Alzheimer's disease	Cleavage product of APP, different lengths including 1–38, 1–40, 1–42, 1–43	Spontaneous under physiological conditions; dominated by secondary nucleation	15 and 16
Tau	Alzheimer's disease and other tauopathies	6 isoforms, heavily phosphorylated in disease	Promoted by the addition of polyanions; dominated by secondary nucleation and/or fragmentation	19 and 38
α-Synuclein	Parkinson's disease and other synucleinopathies	C-terminal cleavage and phosphorylation of S129 and other sites in disease	Slow intrinsic aggregation; promoted by the addition of negatively charged lipid bilayers (primary nucleation), low pH (secondary nucleation) or shaking (fragmentation)	17, 18 and 20–22
Huntingtin (htt) fragments with expanded polyQ	Huntington's diseasea	Aberrant splicing and/or cleavage give rise to N-terminal fragments including exon 1	Simple polyQ stretches and htt exon 1 undergo spontaneous aggregation under physiological conditions; dominated by secondary nucleation; strong dependence on polyQ length	23–25
Islet amyloid polypeptide (IAPP)	Type II diabetes	Mature IAPP is produced from a precursor protein and secreted	Spontaneous aggregation; accelerated by membranes containing anionic lipids	26–30
Superoxide dismutase 1 (SOD1)	Amyotrophic lateral sclerosis (ALS)	Mature protein is a disulfide-crosslinked dimer with copper and zinc ions bound	The apoSOD1 monomer forms fibrils via an unfolded intermediate; fragmentation-driven mechanism under agitation	31–33
Prion protein (PrP)	Creutzfeldt-Jakob disease	Glycosylated and lipid-anchored	Natively folded PrPC is converted into PrPSc through a fragmentation-based mechanism	22

^a9 polyQ expansion diseases are known, which are each associated with polyQ stretches in a different protein.