Sigma-1 receptor agonist PRE084 is protective against mutant huntingtin-induced cell degeneration: involvement of calpastatin and the NF-κB pathway

Abstract

Alterations in mitochondria and increased oxidative stress are associated with the disease progression in Huntington's disease (HD). Endoplasmic reticulum (ER) stress and oxidative damage are linked through the close communication between the ER and mitochondria. Sigma-1 receptor (Sig-1R) is a chaperone protein in the ER that is involved in ER stress regulation, but little is known about its role in HD or the mechanisms for cell protection. Here we show that the Sig-1R agonist, PRE084 increases cell survival and counteracts the deleterious effects caused by N-terminal mutant huntingtin proteins in neuronal PC6.3 cells. Particularly, PRE084 increased the levels of cellular antioxidants by activating the NF-κB pathway that is compromised by the expression of mutant huntingtin proteins. These results show that the Sig-1R agonist has beneficial effects in models of HD and that compounds affecting the Sig-1R may be promising targets for future drug development in HD.

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

“…A recent study indicated that overexpression of Sig-1R or addition of Sig-1R agonist increased endogenous calpain inhibitor calpastatin expression in the neuronal PC6.3 cell line (58). However, we found no significant differences in calpain or calpastatin protein levels in Sig-1R KO neurons or when overexpressing Sig-1R in the neuro-2a cells (Fig.…”

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice

“…In relation to HD, the S1R agonist, PRE084, was shown to enhance cellular antioxidant defences and to protect against mHTT-induced toxicity in a rat neuronal cell line (18). Using R6/2 HD mice, pridopidine treatment was shown to improve motor function and survival, effects that were associated with increased striatal BDNF and DARPP-32 levels (19).…”

“…Alterations in S1R expression levels have been described in different models of HD, suggesting a potential link between S1R and disease pathology (8,18). Treatment with the S1R agonist, PRE084, has been shown to reverse S1R expression levels in PC6.3 neuronal cells and protect against mHTT-induced neurodegeneration (18).…”

“…Treatment with the S1R agonist, PRE084, has been shown to reverse S1R expression levels in PC6.3 neuronal cells and protect against mHTT-induced neurodegeneration (18). Similarly, pridopidine treatment improved motor function and induced neuroprotective effects in the R6/2 mouse model of HD (19).…”

Genesis of ER stress in Huntington’s Disease

“…A recent study showed that another Sigma-1R agonist, PRE084, improved behavioral symptoms in a Parkinson's disease mouse model [191]. In another study, this same agonist promoted cell viability, reduced oxidative stress and decreased cleavage of caspases in mutant Htt-expressing cells [192], suggesting a possible therapeutic benefit of Sigma-1R agonists in HD.…”