Table 2.

Evidence for ER stress and the role of PDI in neurodegenerative diseases.

Neurodegenerative disease	Protein inclusions	Evidence for ER stress	Evidence for a role of PDI
Alzheimer's disease (AD)	β-Amyloid Tau	BiP, PERK, IRE1, and eIF2α upregulated in AD patients (Hoozemans et al., 2005, 2009). Cleaved caspases and JNK upregulated in AD patients (Ghribi et al., 2004; Lee et al., 2010a). CHOP upregulated in AD animal models and cell models treated with β-amyloid, and in AD patients (Ghribi et al., 2004; Chafekar et al., 2008; Lee et al., 2010a). IPSC-derived neurons and astrocytes from AD patients accumulate Aβ oligomers (Kondo et al., 2013).	PDI co-localizes with tau protein (Honjo et al., 2010). PDI levels increase 9.49 fold in tangle-bearing neurons in AD patients (Lee et al., 2010a). β-amyloid co-localizes with ERp57 (Erickson et al., 2005). Pharmacological activation of ERp57 reduces amyloid plaques and neurofibrillary tangles in brains, and improved object recognition memory in AD mouse models (Tohda et al., 2012).
Parkinson's disease (PD)	α-Synuclein	Upregulation of IRE1, PERK, eIF2α, and ATF4 in PD cell models (Ryu et al., 2002). Phosphorylated PERK and phosphorylated eIF2α detected in dopaminergic neurons of PD patients (Hoozemans et al., 2007). Co-localization of phosphorylated PERK and α-synuclein in dopaminergic neurons (Hoozemans et al., 2007). CHOP upregulation in dopaminergic neurons of mouse models and in cell models (Ryu et al., 2002; Holtz and O'Malley, 2003; Silva et al., 2005).	Upregulation of PDIA2 in PD cell models and post-mortem brain tissues of PD patients (Conn et al., 2004). PDIA2 immunoreactivity evident in Lewy Bodies (Conn et al., 2004). PDI upregulated in PD cell models (Ryu et al., 2002).
Amyotrophic lateral sclerosis (ALS)	SOD1 TDP-43 FUS C9orf72	UPR and CHOP induced prior to symptom onset in SOD1G93A mouse models (Atkin et al., 2006; Kikuchi et al., 2006; Saxena et al., 2009). PERK, IRE1 and ATF6 upregulated in post-mortem human spinal cord tissues (Atkin et al., 2008). Deletion of BIM, XBP-1, ASK1, Puma or ATF4 delays disease onset or extends survival in ALS mouse models (Kieran et al., 2007; Nishitoh et al., 2008; Hetz et al., 2009; Matus et al., 2013a,b). Pharmacological inhibition of eIF2α dephosphorylation extends survival of ALS mouse models (Boyce et al., 2005; Saxena et al., 2009).	PDI upregulated in SOD1G93A mouse models at presymptomatic, symptomatic and end stages of disease (Atkin et al., 2006, 2008). PDI co-localizes with inclusions in ALS mouse models, cell models and ALS patients (Atkin et al., 2006, 2008; Tsuda et al., 2008; Honjo et al., 2011; Farg et al., 2012; Walker et al., 2013). PDI and ERp57 upregulated in ALS patient and mouse model spinal cord tissues and patient CSF (Atkin et al., 2006, 2008). PDI over expression decreases mutant SOD1 inclusion formation, BiP and CHOP expression and PERK phosphorylation in ALS cell models (Walker et al., 2010). PDI knock down increases mutant SOD1 inclusion formation in ALS cell models (Walker et al., 2010).
Huntington's disease (HD)	Huntingtin	BiP and CHOP upregulated in post-mortem brains from HD patients and in HD cell models (Duennwald and Lindquist, 2008; Carnemolla et al., 2009). BIM upregulated in HD animal and cells models (García-Martínez et al., 2007; Kong et al., 2009; Leon et al., 2010). XBP-1 upregulated in striatum of HD patients (Vidal et al., 2012). XBP-1 knock down reduced neuron loss and mHtt levels, and improved motor performance in HD mouse models (Vidal et al., 2012).	Increased basal expression of PDI in HD cell models (Duennwald and Lindquist, 2008). PDI elevated in hippocampus of HD mouse models (Safren et al., 2014).
Creutzfeldt-Jakob disease (CJD)	Prion protein	Upregulation of caspase-12 in CJD cell models and post-mortem patient cortex tissues (Hetz et al., 2003). Upregulation of ERp57, Grp94 and BiP in HD cell models and patient cortex tissues (Hetz et al., 2003). Increased intracellular calcium release from the ER (Torres et al., 2010).	PDI overexpression in brains of CJD patients (Yoo et al., 2002). Increased expression of ERp57 (Hetz et al., 2005). ERp57 overexpression protects cells from PrPsc toxicity and decreases rate of caspase-12 activation (Hetz et al., 2005).