Mitochondrial and metabolic dysfunctions in the progeroid Cockayne syndrome and therapeutic perspectives

• Applicant: Professor Dr. Mark-Jürgen Berneburg
• Subject Area: Dermatology ; Biochemistry ; Biogerontology and Geriatric Medicine ; Organic Molecular Chemistry - Synthesis and Characterisation ; Cell Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445959678

Cockayne syndrome (CS) is a rare genetic disease displaying dramatically precocious ageing, severe neurological defects, UV-hypersensitivity, and a short life expectancy with no treatment to date. This project is based on the recent identification and validation of a defective pathway in cells of CS patients that is uncoupled from the well-documented DNA repair defect, and rather involves mitochondrial and metabolic impairment. The extent and the consequences of this metabolic impairment at the molecular and cellular level remain to be elucidated and are the main subject of the present proposal. Importantly, CS displays a wide spectrum of severity that constitutes a clinical continuum the reasons of which are not understood. Our working hypothesis is that metabolic alterations are largely responsible for the different clinical outcomes in CS. Beyond unbalanced energetics, metabolic changes affect regulatory pathways, protection from ROS, and the epigenetic landscape.Our objective is to dissect the metabolic impairment in CS and its consequences on cellfunction, and pave the way to a therapeutic intervention that includes protective effects of metabolism against the aging process. Indeed, the full rescue of CS cellular alterations by a porphyrin derivative acting on oxidative and nitrosative stress, MnTBAP, that we previously demonstrated, is the key element for a novel therapy. MnTBAP obtained an Orphan Drug Designation for CS and is well tolerated in vivo. The present application has three primary aims. Aim1: Link the severity of CS clinical symptoms, and thereby the susceptibility to respond to MnTBAP treatment, to altered mitochondrial parameters. For this, we will assess mitochondrial impairment and its rescue by treatment. Aim 2. Link CS defects with metabolic changes in patient cells using a systematic approach to major metabolic pathways and their protective effect against ROS. Results in patient cells will be integrated with the disease specific scoring system developed by consortium members. Aim 3. Assess the extent of mitochondrial and metabolic alterations on CS-derived iPS cells, neuroectodermal organoids (that only our consortium has produced from CS-iPS cells). On these cells/structures will be applied the abovementioned approaches, and we will consolidate preclinical data on the effect MnTBAP. This project relies on a combination of novel concepts, a unique collection of patient-derived biomaterial, and direct link between research scientists and clinicians to dissect the underlying causes and open to a therapeutic intervention for CS.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partner: Professor Vincent Laugel, Ph.D.