The present invention relates to novel therapeutic ways for treating Wolfram Syndrome (WS) by targeting the neuronal calcium sensor 1 (NCS1). The present invention provides a NCS1-encoding polynucleotide for use in therapy, particularly for use in the treatment of WS, and also relates to an inhibitor of the proteasome for use in the treatment of Wolfram Syndrome. Finally, the present invention also concerns a method for predicting the severity of wolfram syndrome in a patient by measuring the NCS1 level in a sample obtained from said subject, wherein the lower said level of NCS1 is, the higher the patient is predisposed to having severe Wolfram Syndorme.