Table 2.

Examples of therapeutic opportunities for protein condensation diseases

Protein state perturbation	Therapeutic opportunities	Mechanism of action	Examples
Native to amyloid	Antibodies against protein aggregation	Removal of protein aggregates Inhibition of the protein aggregation process	Aβ112,113
	Small molecules against protein aggregation	Stabilisation of the native state Inhibition of the protein aggregation process	TTR111, Aβ109,110
	Small molecules promoting protein degradation	Activation of autophagy and of the ubiquitin–proteasome system to remove aggregating proteins and protein aggregates	mTOR139, PKA140
	Small molecules inhibiting protein synthesis	Inhibition of enzymes required for the production of aggregating proteins	Aβ141
	Small molecules promoting the unfolded protein response	Activation of the unfolded protein response to remove aggregating proteins and protein aggregates, or to inhibit the formation of protein aggregates	PERK142
	Molecular chaperones against protein aggregation	Activation of the protein homoeostasis system to remove protein aggregates or inhibit their formation	Hsp70143
Native to droplet	Small molecules against protein liquid-liquid phase separation	Stabilisation of the native state Perturbation of protein interactions within droplets	SHP2108, M2-145, tau106
	Small molecules promoting protein degradation	Activation of autophagy to remove droplet-forming proteins	tau106
	Small molecules regulating post-translational modifications	Activation of the protein homeostasis system to inhibit droplet formation	FUS144
	Molecular chaperones against protein liquid-liquid phase separation	Activation of the protein homeostasis system to inhibit droplet formation	FUS144
Droplet to native	Small molecules regulating post-translational modifications	Prevention of droplet dissolution	DYRK323
Droplet to amyloid	Small molecules against protein aggregation	Inhibition of the protein aggregation process	α-synuclein145
	Molecular chaperones against protein aggregation	Stabilisation of folded protein domains within droplets	FUS116
	Molecular chaperones regulating cellular localisation	Re-localisation of nuclear RNA-binding proteins	FUS, hnRNPA1, hnRNPA2117
Amyloid to native	Small molecules against the conversion to the native state	Stabilisation of the functional amyloid state	Currently not known
Amyloid to droplet	Small molecules promoting droplet hardening	Stabilisation of the functional amyloid state	Currently not known

We anticipate that many approaches developed for the prevention of the conversion between the native and the amyloid states will be applicable to the conversion between the native and droplet states, as well as between the droplet and amyloid states. Since for diseases associated with the conversion of the amyloid state into the native or droplet state there are no currently known examples of therapeutic approaches, we suggested possible mechanisms of action (in italics).