Table 2.
Restoring protein homeostasis as a treatment for ALS.
| Target | Treatment | Effect on proteostasis | Effect on disease | Reference |
|---|---|---|---|---|
| HSF-1 | Arimoclomol | Stabilizes HSF-1. Upregulation of chaperones | Delays disease progression and increases lifespan in SOD1G93A mice | Kieran et al., 2004; Kalmar et al., 2008 |
| Hsp90 | 17-AAG | Hsp90 inhibition and Hsp70 activation | Reduces TDP-43 aggregates in HEK293 cells | Chang et al., 2013 |
| UPR/eIF2α | Salubrinal | eIF2a maintained in active state and persistence of UPR | Protection of SOD1G93A mice MN from ER stress | Boyce et al., 2005 |
| UPR/eIF2α | Guanabenz | eIF2a maintained in active state and persistence of UPR | Delayed disease onset, extended lifespan and reduced MN loss of SOD1G93A mice | Tsaytler et al., 2011 |
| Chronic UPR | XBP-1 knockout | Inhibition of UPR. Increased autophagic clearance | Extends survival in SOD1G86R mice and reduced SOD1 aggregation | Hetz et al., 2009 |
| Chronic UPR | ATF4 knockout | Complete inhibition of UPR pro-apoptotic gene expression | Delayed disease onset and extends survival in SOD1 G86R mice. Increased SOD1 aggregation | Matus et al., 2013 |
| UPS | Pyrazolone | Proteasome activation | Reduced SOD1G93A cytotoxicity and aggregation | Chen et al., 2012; Trippier et al., 2012; Zhang et al., 2013 |
| Autophagy | Fluphenazine methotrimeprazineNCP | Autophagy induction | Enhance mutant TDP-43A315T clearance, improved survival of murine primary cortical neurons overexpressing TDP-43A315T | Barmada et al., 2014 |
| Autophagy | Berberine | Autophagy induction | Increased clearance of aggregate prone TDP-43 fragments in N2a cells | Chang et al., 2016 |
| Autophagy | Rapamycin/tamoxifen | mTOR dependent autophagy induction | Reduces TDP-43 aggregation, rescues memory/learning and slow motor deficits in FTLD-U mouse | Wang et al., 2012 |
| Autophagy | Spermidine/carbamazepine | mTOR independent autophagy induction | Reduced TDP-43 aggregation, increased memory/learning and reduced slow motor deficits in FTLD-U mouse | Wang et al., 2012 |
| Autophagy | Trehalose | mTOR independent autophagy induction | Reduced SOD1G85R aggregation in spinal cord of SOD1G85R mice, delaying onset and increasing lifespan | Castillo et al., 2013; Zhang X. et al., 2014; Li et al., 2015 |
MN, motor neurons.