TABLE 2.

Therapeutics targeting either the UPR^ER or the UPR^mt, their mechanisms of action, and their effects in various model systems.

Therapeutic	UPR target and mechanism of action	Effect(s)	Model(s)	References
Salubrinal	↑ PERK-UPRER Inhibits eIF2α dephosphorylation	Rescues motor impairment, reduces mortality	Mutant SOD1-expressing ALS mice	Saxena et al., 2009
		Confers neuroprotection	Aβ-expressing human neuronal cells	Lee et al., 2010a
		Exacerbates neuronal loss, reduces lifespan	Prion-infected mice	Moreno et al., 2012
		Decreases α-syn accumulation, rescues motor impairment	α-syn-expressing PD mice and rats	Colla et al., 2012
		Confers neuroprotection	Rotenone-induced PD human neuronal cells	Wu et al., 2014
Guanabenz	↑ PERK-UPRER Inhibits eIF2α dephosphorylation	Promotes clearance of abnormal prions (PrPSc)	Yeast and prion-infected mouse Schwann cells	Tribouillard-Tanvier et al., 2008
		Delays disease progression, reduces mortality	Mutant SOD1-expressing ALS mice	Jiang et al., 2014; Wang et al., 2014b
		Accelerates disease progression	Mutant SOD1-expressing ALS mice	Vieira et al., 2015
		Ameliorates pathology	Mutant SOD1-expressing ALS mice	Das et al., 2015
		Extends lifespan	Prion-infected mice	Thapa et al., 2020
GSK2606414	↓ PERK-UPRER Inhibits PERK activation	Confers neuroprotection	Prion-infected mice	Moreno et al., 2013
		Lowers p-tau, confers neuroprotection	Mutant tau-expressing FTD mice	Radford et al., 2015
		Confers neuroprotection but also causes pancreatic toxicity	Neurotoxin-induced PD mice	Mercado et al., 2018
ISRIB	↓ PERK-UPRER Reverses phosphorylation of eIF2α	Confers neuroprotection	Prion-infected mice	Halliday et al., 2015
		Confers neuroprotection	Mutant SOD1-expressing ALS rat neuronal cells	Bugallo et al., 2020
		Rescues memory impairment	Wild-type mice	Krukowski et al., 2020
Trazodone	↓ PERK-UPRER Inhibits p-eIF2α signaling	Confers neuroprotection	Prion-infected mice, mutant tau-expressing FTD mice	Halliday et al., 2017
IXA1/IXA4/IXA6	↑ IRE1α-UPRER Specifically activates IRE1-dependent XBP1 signaling	Reduces Aβ levels (IXA4) and reduces APP secretion (IXA4/6)	Mutant APP-expressing AD hamster cells	Grandjean et al., 2020
Doxycycline	↑ ATF5-UPRmt Induces mito-nuclear imbalance	Extends lifespan	Wild-type C. elegans	Houtkooper et al., 2013
		Confers neuroprotection, reduces mortality	Aβ-expressing C. elegans	Sorrentino et al., 2017
Chloramphenicol	↑ ATF5-UPRmt Induces mito-nuclear imbalance	Extends lifespan	Wild-type C. elegans	Houtkooper et al., 2013
Nicotinamide riboside	↑ ATF5-UPRmt Induces mito-nuclear imbalance, and ↑ SIRT3-UPRmt Increases [NAD+]	Extends lifespan	Wild-type yeast	Belenky et al., 2007
		Extends lifespan	Wild-type C. elegans	Mouchiroud et al., 2013
		Confers neuroprotection, reduces mortality	Aβ-expressing C. elegans	Sorrentino et al., 2017
		Reduces Ab toxicity, rescues memory impairment	Mutant APP- and PSEN1-expressing AD mice	Sorrentino et al., 2017
Nicotinamide mononucleotide	↑ ATF5-UPRmt Likely induces mito-nuclear imbalance, and ↑ SIRT3-UPRmt Increases [NAD+]	Extends lifespan	Wild-type C. elegans	Mouchiroud et al., 2013
		Confers neuroprotection	Mutant PINK1-expressing PD D. melanogaster	Lehmann et al., 2017
Olaparib (also called AZD2281)	↑ ATF5-UPRmt Induces mito-nuclear imbalance, and ↑ SIRT3-UPRmt Increases [NAD+]	Extends lifespan	Wild-type C. elegans	Mouchiroud et al., 2013
		Confers neuroprotection, reduces mortality	Aβ-expressing C. elegans	Sorrentino et al., 2017
Resveratrol	↑ ATF5-UPRmt Induces mito-nuclear imbalance, and ↑ SIRT3-UPRmt Activates sirtuins	Extends lifespan	Wild-type C. elegans	Houtkooper et al., 2013
		Confers neuroprotection	Aβ-expressing C. elegans	Regitz et al., 2016