Mol Ther Methods Clin Dev. 2022 Oct 7;27:295-308. doi: 10.1016/j.omtm.2022.10.003. eCollection 2022 Dec 8.
Wolfram syndrome (WS) is a rare neurodegenerative disease resulting in deafness, optic atrophy, diabetes, and neurological disorders. Currently, no treatment is available for patients. The mutated gene, WFS1, encodes an endoplasmic reticulum (ER) protein, Wolframin. We previously reported that Wolframin regulated the ER-mitochondria Ca2+ transfer and mitochondrial activity by protecting NCS1 from degradation in patients’ fibroblasts. We relied on a zebrafish model of WS, the wfs1ab KO line, to analyze the functional and behavioral impact of NCS1 overexpression as a novel therapeutic strategy. The wfs1ab KO line showed an increased locomotion in the visual motor and touch-escape responses. The absence of wfs1 did not impair the cellular unfolded protein response, in basal or tunicamycin-induced ER stress conditions. In contrast, metabolic analysis showed an increase in mitochondrial respiration in wfs1ab KO larvae. Interestingly, overexpression of NCS1 using mRNA injection restored the alteration of mitochondrial respiration and hyperlocomotion. Taken together, these data validated the wfs1ab KO zebrafish line as a pertinent experimental model of WS and confirmed the therapeutic potential of NCS1. The wfs1ab KO line therefore appeared as an efficient model to identify novel therapeutic strategies, such as gene or pharmacological therapies targeting NCS1 that will correct or block WS symptoms.