8th International Wolfram Symposium Presentation Dr Benjamin Delprat – University of Montpellier, France
8th International Wolfram Symposium Presentation Dr Benjamin Delprat – University of Montpellier, France
Advances on the pharmacological and gene therapies approaches
Abstract: Wolfram syndrome is a rare autosomal recessive disease affecting many organs with life-threatening consequences and currently no treatment is available. Therefore, the need to find a cure is imperative. The pathology is related to the deficient activity of wolframin, an endoplasmic reticulum (ER) transmembrane protein were shared from Estonia (Dr Mario Plaas). Final time point studied 7.5 months. Some changes detected very early (from 3 months). involved in contacts between ER and mitochondria termed mitochondria associated- ER membranes (MAMs). Inherited mutations usually reduce the protein’s stability, altering its homeostasis and ultimately reducing ER to mitochondria Ca2+ transfer resulting in mitochondrial dysfunction and cell death. We previously demonstrated that improving MAMs functioning by overexpressing NCS1, a wolframin partner, is efficient in correcting the cellular and behavioral alterations in our preclinical models of the pathology.
Based on these data, we focused our research on another crucial protein of the MAMs physiology, the sigma-1 receptor (S1R), an endoplasmic reticulum resident protein involved in Ca2+ transfer. Very interestingly, S1R could be activated by small active molecules to foster the Ca2+ transfer between ER and mitochondria. Therefore, we demonstrated that activation of S1R with the prototypic agonist PRE-084, restored Ca2+ transfer and mitochondrial respiration in vitro, corrected the associated increased autophagy and mitophagy, and was able to alleviate the behavioral symptoms observed in the genetic animal models of the disease, i.e. hyperlocomotion in wfs1abKO zebrafish and memory deficits and anxiety in Wfs1∆Exon8 mice. Our findings provide a new therapeutic strategy for Wolfram syndrome patients, by efficiently boosting MAM function using the ligand operated S1R chaperone.
Points noted:
• NCS-1 (neuronal calcium sensor -1) represents a relevant target for treating WS.
• Activation of S1R is beneficial in WS – (e.g. improved memory and increased Ca2+ in WS models).
• S1R targeting is therefore relevant for WS patients.
• NCS-1 modulators / stabilizers were not investigated.