Ploumi, Christina et al. (2019) International Worm Meeting "A C. elegans model for Wolfram Syndrome type 2."

Kyriakakis, Emmanouil, Tavernarakis, Nektarios, Ploumi, Christina

[International Worm Meeting, 2019]

Wolfram Syndrome (WS) is a rare neurodegenerative disorder, the patients of which are very early diagnosed with diabetes, optic atrophy and deafness, while their life expectancy is around 30 years due to systemic complications. Two types of WS have been characterized; Type 1 is caused by mutations in the WFS1 gene encoding the ER-localized protein Wolframin, while Type 2 is caused by mutations in the Cisd2 gene. Cisd2 gene encodes a mitochondrial iron-sulfur cluster (ISC) binding protein which belongs to the NEET protein family. Importantly, it is not well understood how loss of the particular ISC binding protein leads to WS pathophysiology in humans. The C. elegans gene cisd-1 (W02B12.15) encodes a functional homolog of the mammalian NEET protein CISD2, based on sequence analysis and the presence of the conserved domain CDGSH for binding to ISCs. Downregulation of cisd-1 through RNAi recapitulates key features of CISD2 loss, associated with WS type 2, including short life expectancy and enhanced neurodegeneration. Based on our findings, CISD-1 exerts differential effects on longevity and healthspan, through its involvement in both the intrinsic apoptosis pathway and the autophagic process. The CISD-1- dependent effects on apoptosis and autophagy seem to be affected by intracellular iron levels, suggesting that CISD-1 deficiency may disturb intracellular iron homeostasis. Our work will facilitate the elucidation of the molecular mechanisms underlying WS pathogenesis and provide critical insights towards the development of effective therapeutic strategies.

Kyriakakis, Emmanouil et al. (2017) International Worm Meeting "A C. elegans model of Wolfram Syndrome type 2."

Tavernarakis, Nektarios, Ploumi, Christina, Kyriakakis, Emmanouil

[International Worm Meeting, 2017]

Wolfram syndrome (WS) is a rare autosomal neurodegenerative disorder, characterized by early juvenile diabetes mellitus, a gradual loss of vision due optic nerve atrophy, deafness and often behavioral and mental changes. The average life expectancy is 30 years due to systemic complications. Treatment is merely symptomatic and supportive. There are two genetics forms of WS; type 1 is caused by mutations in the WFS1 (wolframin) gene, whereas WS type 2 is caused by mutations in the CISD2 gene. The C. elegans cisd-1 gene encodes a homolog of the mammalian CISD2, based on sequence analysis and the presence of the conserved iron sulfur domain. Lesion of cisd-1 recapitulates key features of CISD2 loss associated with WS type 2, including lifespan shortening and neurodegeneration. Intriguingly, dietary restriction (DR) completely reverses the detrimental effects of CISD-1 deficiency on longevity. This effect is at least in part due to autophagy induction. In addition, cellular proteostasis mechanisms are deferentially affected by CISD-1. The mitochondrial unfolded protein response (UPRmito) is significantly suppressed, while the endoplasmic reticulum UPRER is upregulated during ER stress. The heat shock response remains unaffected. These findings suggest an involvement of CISD-1 in organelle-specific proteome homeostasis. The C. elegans WS model will facilitate elucidation of the molecular mechanisms underlying WS pathogenesis and provide a platform for drug discovery.

Christina Dittrich et al. (2006) European Worm Meeting "Identifying Novel Genes Involved in DNA Damage Response Pathways in C. elegans"

Michael O. Hengartner, Christina Dittrich

[European Worm Meeting, 2006]

Christina Dittrich and Michael O. Hengartner1. Upon DNA damage, a cell responds by arresting its cell cycle, changing its transcription patterns, recruiting the repair machinery or, most severely, by executing its own death by apoptosis. Malfunction of any of these pathways allows cells to replicate in spite of DNA lesions, and thus their genomes accumulate mutations and becomes unstable, a hallmark of tumor cells. Therefore, it is not only of paramount biological, but also of high medical interest, to understand the molecular pathways underlying DNA damage responses. Genotoxic stress induces in the germ line of Caenorhabditis elegans a spectrum of DNA damage responses similar to that observed in humans. Because important genes are often conserved throughout evolution, studies in C. elegans might improve our understanding of the molecular programmes safeguarding the genome of human cells. Wild-type C. elegans animals carry out proper DNA damage responses following exposure to ionizing radiation (IR), thus most of their progeny survive. In contrast, radiation-sensitive (Rad) mutants, which are defective in these pathways, show high levels of embryonic lethality upon IR. Taking advantage of this phenotype, we performed a forward genetic screen and identified 17 mutants whose embryos show reduced viability following IR treatment. Two of those mutants, op442 and op444, display a strong Rad phenotype. We are currently mapping the affected genes taking advantage of molecular polymorphisms between the Bristol and the Hawaii isolate of C. elegans. Additionally, we are characterising those two mutants further in order to learn more about the molecular nature underlying the observed defects.