Neuronal Calcium Sensor 1 (NCS1) as a Potential Drug Target for Treatment of Wolfram Syndrome

Publication: The Faseb Journal | Publication Date: April 15, 2020

Authors: Tom T. Fischer, Lien D. Nguyen, Barbara E. Ehrlich

Abstract

Wolfram syndrome (WS) is an orphan, autosomal recessive neuroendocrinological disease that affects approximately 1 in 500,000 people worldwide. Patients develop diabetes mellitus, diabetes insipidus, optical atrophy, and hearing loss and usually die in their 30s. The majority of cases are attributed to mutations in a single gene, WFS1, which encodes for the protein wolframin. Despite the known genetic cause, there is currently no direct treatment for WS. This lack of therapy is because the regular functions of wolframin, and the pathophysiological consequences following the loss of intact WFS1, remain elusive. Here, we further examined the function of WFS1 in the context of glucose toxicity, to address the earliest diagnosed symptom of WS which is the onset of diabetes mellitus near age 6. Based on a recent study [1], we aimed to show that WFS1 interaction with a calcium binding protein, neuronal calcium sensor 1 (NCS1), is important for its normal functions. NCS1 is known to regulate exocytosis, promote cell survival, and maintain calcium homeostasis. We showed that knocking out WFS1 in rat insulinoma (INS1) cells resulted in increased baseline calcium, reduced ATP-evoked inositol-trisphosphate receptor (InsP3R)-dependent calcium response, reduced phospho-Akt (Ser473), and increased vulnerability to high glucose treatment. Furthermore, both INS1 control (CTRL) and WFS1 knockout (KO) cells showed increased NCS1 mRNA following high glucose treatment. However, only the CTRL cells showed increased NCS1 protein expression, whereas WFS1 KO cells showed decreased NCS1 expression. These results suggest that NCS1-WFS1 interaction protects NCS1 from degradation, potentially by the calcium-dependent protease calpain. Lastly, we showed that overexpression of NCS1, or treatment with a putative NCS1-binding drug, rescued the deficits observed in WFS1 KO cells. Overall, we demonstrated a physiological function of the WFS1-NCS1 interaction and that protecting NCS1 levels can ameliorate the deficits caused by loss of WFS1. These findings will facilitate the discovery of drugs that can prevent or reduce the symptoms of WS.

Fischer, T.T., Nguyen, L.D. and Ehrlich, B.E. (2020), Neuronal Calcium Sensor 1 (NCS1) as a Potential Drug Target for Treatment of Wolfram Syndrome. The FASEB Journal, 34: 1-1. Retrieved February 13, 2024, from https://doi.org/10.1096/fasebj.2020.34.s1.00556.