Table 1.

Protein folding diseases impacted by UPR-dependent modulation of secretory proteostasis

Protein	Disease	Pathophysiology	Correction by targeting secretory proteostasis		Ref
			Pathway targeted	Outcome
Gain-of-toxicity (aggregation) diseases
TTR	Senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP)	Extracellular aggregation and amyloid formation of WT (age-related) or destabilized mutant variants of TTR	ATF6 activation	Reduced secretion, increased degradation, co-secretion with ERdj3 co-chaperone	[17, 38, 43, 76]
Light Chain (LC)	LC Amyloidosis (AL)	Extracellular aggregation, amyloid formation of destabilized LC sequences	ATF6 activation XBP1s activation	Reduced secretion, increased ER chaperone interactions Reduced secretion, increased proteosomal and lysosmal degradation	[39, 76]
Rhodopsin	Retinal degeneration	Cellular toxicity in retinal cells due to intracellular aggregate formation, developmental defects	ATF6 activation; IRE1 activation	Reduced trafficking and intracellular aggregation through increased targeting to ERAD or lysosomal degradation	[40, 41]
α1-antitrypsin (A1AT)	A1AD-associated emphyse ma, liver cirrhosis	A1AT deficiency due to intracellular aggregate formation of destabilized variants	ATF6 activation	Decreased intracellular aggregates, increased ERAD or autophagy	[42]
Loss-of-function diseases
β-glucocerebrosidase (GC)	Gaucher Disease	Pre-mature degradation of destabilized variants and loss of lysosomal enzyme function, abnormal accumulation of glucocerebroside	ERAD inhibition (modulation of ER Ca(II) homeostasis); ER stress (IRE1 activation)	Enhancement of folding of mutant GC variants, trafficking, and lysosomal activity	[29, 32, 92]
α-galactosidase	Fabry Disease	Pre-mature degradation of destabilized variants and loss of lysosomal enzyme function, abnormal accumulation of globotriaosylceramide
γ-aminobutyric acid, Type A (GABAA) receptor	Idiopathic epilepsy	Excessive degradation of destabilized variants, reduced trafficking to plasma membrane, deficiency in excitatory-inhibitory balance of neurons	Inhibition of VCP (component of ERAD); Inhibition of ER Ca(II) receptors	Prevents degradation and enhances the trafficking of destabilized mutant α1-subunit containing GABAA receptors to plasma membrane, rescues receptor function	[31, 93, 94]