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.

Kyriakakis, Emmanouil et al. (2015) International Worm Meeting "Adiponectin receptors couple protein homeostasis and cellular metabolism to modulate ageing in C. elegans."

Tavernarakis, Nektarios, Kyriakakis, Emmanouil

[International Worm Meeting, 2015]

The metabolic and endocrine functions of adipose tissue as well as the ability of organisms to cope with cellular stress have a direct impact on physiological ageing and the etiology of various diseases such as obesity-related pathologies, neurodegenerative conditions and cancer. The endocrine effects of adipose tissue are mediated by secreted adipose-derived hormones, known as adipokines (e.g. adiponectin), which modulate metabolic processes and influence related maladies. It is postulated that tissue and organ communication may alter organismal longevity via endocrine pathways, by coupling physiological pathways which regulate ageing. Additionally, age-related pathologies ensue when an organism loses the capacity to adapt to stress during ageing. Although a large number of molecules and signaling pathways associate ageing with proteotoxic stress and cellular metabolism, how these pathways interact to coordinate organismal physiology is not well-understood. We exploit the experimental versatility of C. elegans to dissect the mechanisms linking adipose-tissue hormone-mediated pathways and endoplasmic reticulum (ER) stress responses that individually or synergistically affect longevity. We find that lesion in the three adiponectin receptor homologues (PAQR-1, PAQR-2 and PAQR-3), cause opposing effects on ER stress resistance. Notably, PAQR-1 deficient animals strongly respond to ER stress, by rapidly activating the canonical ER unfolded protein response (UPRER) pathway. These mutants exhibit enhanced adaptation to stress, and as a result, their survival improves under precarious conditions. Furthermore, we observed reduced accumulation of lipids during ageing and under ER stress conditions in these animals. This effect is directly related to stress resistance conferred by the adiponectin receptor deficiency. Our findings, for the first time, couple proteotoxic stress and fat homeostasis mechanisms to influence the ageing process. Further elucidation of the molecular specifics that control and link such mechanisms may facilitate the development of specific pharmacological strategies for the treatment of multiple age-associated conditions.

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.