Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models

Abstract

The Wolfram syndrome is a rare autosomal recessive disease affecting many organs with life-threatening consequences; currently, no treatment is available. The disease is caused by mutations in the WSF1 gene, coding for the protein wolframin, an endoplasmic reticulum (ER) transmembrane protein involved in contacts between ER and mitochondria termed as mitochondria-associated ER membranes (MAMs). Inherited mutations usually reduce the protein’s stability, altering its homeostasis and ultimately reducing ER to mitochondria calcium ion transfer, leading to mitochondrial dysfunction and cell death. In this study, we found that activation of the sigma-1 receptor (S1R), an ER-resident protein involved in calcium ion transfer, could counteract the functional alterations of MAMs due to wolframin deficiency. The S1R agonist PRE-084 restored calcium ion transfer and mitochondrial respiration in vitro, corrected the associated increased autophagy and mitophagy, and was able to alleviate the behavioral symptoms observed in zebrafish and mouse models of the disease. Our findings provide a potential therapeutic strategy for treating Wolfram syndrome by efficiently boosting MAM function using the ligand-operated S1R chaperone. Moreover, such strategy might also be relevant for other degenerative and mitochondrial diseases involving MAM dysfunction.

Wolfram Syndrome 1: From Genetics to Therapy

“…In particular, the agonist S1R PRE-084 restored calcium transfer, improved mitochondrial respiration, and modified autophagy and cellular mitophagy, thus ameliorating symptoms in zebrafish and rodents. These data suggest that S1R chaperone may be a potential drug for the therapy of WS1 [ 83 ]. Although they are a promising class of therapeutic drugs for WS1, the need to use high concentrations of chemical chaperones limits their use.…”

Dysregulated Ca2+ Homeostasis as a Central Theme in Neurodegeneration: Lessons from Alzheimer’s Disease and Wolfram Syndrome

“…At the MAMs, Wfs1 interacts with S1R, which similarly to NCS1 can also positively modulate ER–mitochondrial Ca 2+ transfer. Stimulation of S1R with PRE-084, a S1R agonist, could overcome the Wfs1-deficiency-mediated decrease in IP 3 R-mediated Ca 2+ release and ER–mitochondrial Ca 2+ transfer [ 175 ]. The PRE-084, could also alleviate mitochondrial abnormalities associated with reduced MAM functionality, such as increased mitophagy [ 175 ].…”

“…Stimulation of S1R with PRE-084, a S1R agonist, could overcome the Wfs1-deficiency-mediated decrease in IP 3 R-mediated Ca 2+ release and ER–mitochondrial Ca 2+ transfer [ 175 ]. The PRE-084, could also alleviate mitochondrial abnormalities associated with reduced MAM functionality, such as increased mitophagy [ 175 ]. Additionally, WS1 is linked with impaired mitochondrial dynamics, as knocking down the Wfs1 in neurons decreased the mitochondrial mass, mobility and fusion, while increasing the rate of mitophagy [ 154 ].…”

“…S1R resides at MAMs where it acts on IP 3 Rs and regulates the Ca 2+ signaling and survival [ 42 ]. The WFS1 was reported to interact with the S1R and therefore to positively modulate the ER–mitochondrial Ca 2+ transfer [ 175 ]. Stimulation with a S1R agonist could counteract the impaired Ca 2+ homeostasis and mitochondrial deficits observed in WS [ 175 ].…”

“…The WFS1 was reported to interact with the S1R and therefore to positively modulate the ER–mitochondrial Ca 2+ transfer [ 175 ]. Stimulation with a S1R agonist could counteract the impaired Ca 2+ homeostasis and mitochondrial deficits observed in WS [ 175 ]. However, also in AD, S1R is emerging as a novel target.…”