Brain cell death in rare disease Wolfram syndrome linked to mitochondrial defects

The Sarkar and Barrett labs have defined the molecular basis of neurodegeneration in Wolfram Syndrome patients carrying the WFS1 gene mutation.

Microscopy images of disease-affected neurons generated from Wolfram syndrome patient-derived induced pluripotent stem cells, showing neuronal and cell death markers (left and right panels); Schematic representation of genetic and chemical rescue of mitochondrial dysfunction in Wolfram syndrome (middle panel).

In a study published in Stem Cell Reports the Sarkar and Barrett labs have defined the molecular basis of neurodegeneration in Wolfram Syndrome patients carrying the WFS1 gene mutation.

Wolfram Syndrome is a rare childhood-onset neurodegenerative disease caused by mutations in WFS1 gene and is associated with brain and optic nerve atrophy, diabetes and deafness. Here the research team led by Dr Sovan Sarkar and Professor Timothy Barrett, in collaboration with Dr Laetitia Aubry at I-STEM in France, has generated brain cells called neurons from patient-derived induced pluripotent stem cells to investigate the molecular basis of neurodegeneration underlying Wolfram syndrome. The researchers show that mutations causing loss of function of the WFS1 gene lead to wide-ranging defects in mitochondrial function including a decrease in ATP production and an increase in oxidative stress, ultimately leading to neuronal cell death.

WFS1 is a component of the interaction domains between the mitochondria and endoplasmic reticulum (ER) that are involved in the regulation of mitochondrial biogenesis and dynamics. Depletion of WFS1 protein in Wolfram syndrome leads to a breakdown in communication between the ER and mitochondria. In this study led by Dr Malgorzata Zatyka, a senior research fellow in Sarkar and Barrett labs, WFS1 is shown to interact with VDAC1 in mitochondria whereas this interaction is abolished in Wolfram syndrome that could reduce ER-mitochondria contacts and affect mitochondrial dynamics and function.

The researchers show that genetic correction by restoration of WFS1 levels reinstates WFS1-VDAC1 interaction and increases ER-mitochondria communications, which is associated to the recovery of mitochondrial function and dynamics, and amelioration of neuronal cell death. They further show that pharmacological agents modulating mitochondrial function improve mitochondrial bioenergetics and survival of Wolfram syndrome patient-derived neurons.

Dr Sovan Sarkar, who is the lead senior author of this study, said: 

We have utilized disease-affected cellular platforms from Wolfram syndrome patients for disease modelling and drug testing that are of biomedical relevance to gain insights for future clinical translation. In patient-derived cortical neurons exhibiting depletion of WFS1, we show that failure of mitochondria to properly carry out their normal function contributes to neuronal cell death. Our study highlights a potential therapeutic intervention for WS and related rare diseases with mitochondrial defects. At a fundamental level, we describe a role of WFS1 in regulating mitochondrial function that could be likely due to its interaction with VDAC1 that we have identified.

Dr Sovan Sarkar, Birmingham Fellow

For many years, the rare neurodegeneration and diabetes disease, Wolfram syndrome, was thought to be a mitochondrial genetic disorder as it predominantly affects organs with a large energy dependence (brain, pancreatic beta cells, vision and hearing). However UoB researchers demonstrated in the 1990s that the disease gene localised to chromosome 4 in the nucleus. With this paper, Sarkar et al finally explain the link with mitochondria, showing how depletion of the Wolfram syndrome gene compromises mitochondrial function. This research opens up new avenues for therapy development by targeting the mitochondria, and has implications for common forms of neurodegeneration and diabetes.

Professor Timothy Barrett, Director of Centre for Rare Disease Studies

Dr Sarkar collaborates with Professor Barrett as part of the Centre for Rare Disease Studies in the Institute of Cancer and Genomic Sciences. Their overarching goal is to find shared patho-mechanisms in rare early-onset neurodegenerative diseases using clinically relevant experimental platforms, and targeting those biological pathways for devising a common therapeutic intervention.

Stem Cell Reports 18:1090-1106 (2023). Zatyka M, TR Rosenstock, C Sun, AM Palhegyi, GW Hughes, S Lara-Reyna, D Astuti, A di Maio, A Sciauvaud, ME Korsgen, V Stanulovic, G Kocak,M Rak, S Pourtoy-Brasselet, K Winter, T Varga, M Jarrige, H Polveche, J Corrieia, E-M Frickel, M Hoogenkamp, DG Ward, L Aubry, T Barrett and S Sarkar. Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome.