Seminar by Prof. Rachel Nechushtai
The Hebrew University of Jerusalem (Israel)
The NAF-1 protein is the causative of the Neurodegenerative Progressive disease Wolfram Syndrome 2
NAF-1 is a [2Fe-2S] protein involved in numerous diseases, e.g. diabetes, cancer, aging and neurodegeneration, probably due to its involvement in Fe/Fe-S/Redox/Ca+2 homeostasis1. NAF-1 has homodimeric structure with the unique “NEET fold” and labile [2Fe-2S] clusters coordinated by 3Cys:1His (His114)2,3. Molecular dynamics along with quantum chemical calculations showed that the protonation of the histidine leads to the cluster loss, which is associated with a dramatic decrease NAF-1 structure, which disrupts the protein function4. A homozygous mutation in the NAF-1 encoding gene, cisd2, causes the Neurodegenerative progressive disease Wolfram Syndrome Type-25. The single missense mutation at nucleotide 109 where G is substituted with C (G109C), leads to exon skipping, frame shift and premature stop codon that results in the absence of the NAF-1 protein. This mutation is highly abundant (1:40) in our regional Palestinian populations. WFS-T2 patients suffer, among other pathologies, from optical nerve atrophy, sensorineural hearing loss, psychiatric episodes and b-cell dysfunction. To avoid these pathophysiological situations, we tested treatments of an iron chelator with/without antioxidant agent on skin fibroblasts obtained from four WFS-T2 patients. The results that will be presented in the talk, show that the combed therapy (iron chelation & anti-oxidant), induced a correction of the some of the pathophysiological disorders in the WFS-T2 patient6. Yet, additional novel drugs are needed to be designed to fully manage the WFS-T2 disease.
BIBLIOGRAPHY
1. Sohn, Y. S.; Tamir, S.; Song, L.; Michaeli, D.; Matouk, I.; Conlan, A. R.; Harir, Y.; Holt, S. H.; Shulaev, V.; Paddock, M. L.; Hochberg, A.; Cabanchick, I. Z.; Onuchic, J. N.; Jennings, P. A.; Nechushtai, R.; Mittler, R., NAF-1 and mitoNEET are central to human breast cancer proliferation by maintaining mitochondrial homeostasis and promoting tumor growth. Proc Natl Acad Sci U S A (2013) 110 (36), 14676-81.
2. Karmi, O.; Marjault, H.-B.; Pesce, L.; Carloni, P.; Onuchic, J. N.; Jennings, P. A.; Mittler, R.; Nechushtai, R., The unique fold and lability of the [2Fe-2S] clusters of NEET proteins mediate their key functions in health and disease. JBIC Journal of Biological Inorganic Chemistry (2018) 23(4) 1-14.
3. Darash-Yahana, M.; Pozniak, Y.; Lu, M.; Sohn, Y. S.; Karmi, O.; Tamir, S.; Bai, F.; Song, L.; Jennings, P. A.; Pikarsky, E.; Geiger, T.; Onuchic, J. N.; Mittler, R.; Nechushtai, R., Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters. Proc Natl Acad Sci U S A (2016).113 (39),, 10890-10895.
4. Pesce, L.; Calandrini, V.; Marjault, H. B.; Lipper, C. H.; Rossetti, G.; Mittler, R.; Jennings, P. A.; Bauer, A.; Nechushtai, R.; Carloni, P., Molecular Dynamics Simulations of the [2Fe-2S] Cluster-Binding Domain of NEET Proteins Reveal Key Molecular Determinants That Induce Their Cluster Transfer/Release. J Phys Chem B (2017) 121 (47), 10648-10656.
5. Amr, S.; Heisey, C.; Zhang, M.; Xia, X. J.; Shows, K. H.; Ajlouni, K.; Pandya, A.; Satin, L. S.; El-Shanti, H.; Shiang, R., A homozygous mutation in a novel zinc-finger protein, ERIS, is responsible for Wolfram syndrome 2. Am J Hum Genet 2007, 81 (4), 673-683.
6. Karmi, O. Abdulhag, U.N., Sohn, Y.S. Klopstock, T., Lobel., O., Abu Libdeh, A., Wilchansky, M., Abbasi, M.,. Leibowitsch,, G., Mittler, R., Cabantchik, I.Z, Atwan, M., Weinberg-Shukron, A., Levy-Lahad, E., Renbaum, P., Zangen, D. Nechushtai, R. A novel combined therapy for Wolfram Syndrome Type 2 Patients; From cellular model systems to patient treatment. Science Translational Medicine, (2019), submitted.