Wolfram syndrome

Team:

Laetitia Aubry : Assistant Professor (UEVE)

Sandra Pourtoy : Associate engineer (CECS)

Axel Sciauvaud : PhD student

Aims and background:

Wolfram syndrome type 1 (WS) is a rare neurodegenerative disorder characterized by childhood onset diabetes, optic nerve atrophy, deafness, and various neurological defects. The visual defect is the consequence of a selective and progressive loss of retinal ganglion cells (RGCs). Most of the brain dysfunctions include cerebellar ataxia, cognitive impairment, nystagmus, dysphagia, and central sleep apneas. To date, despite the scientific advances achieved in the past years, there is no therapeutic solution to slow or stop this devastating disorder. A major challenge in studying the molecular pathological mechanisms underlying any neurodegenerative disorders is the limited experimental access to disease-affected human nervous system tissue. In vitro disease modeling using embryonic stem cells or induced pluripotent stem cells (iPSCs) has shown considerable potential for applications in drug discovery, as well as for the elucidation of disease mechanisms. Thus in this context, over the past years we have developed a research program dedicated to the pathological modeling of WS using iPS cells and their derivatives. The overall goal of this project is to better understand the pathomechanisms underlying the neurological and visual defect in order to develop a pharmacological therapeutic solution for the patients.

Publications:

• Human iPSC-derived neurons reveal early developmental alteration of neurite outgrowth in the late-occurring neurodegenerative Wolfram syndrome.  Am J Hum Genet. 2021 Nov 4;108(11):2171-2185.
  Pourtoy-Brasselet S, Sciauvaud A, Boza-Moran MG, Cailleret M, Jarrige M, Polvèche H, Polentes J, Chevet E, Martinat C, Peschanski M, Aubry L.
  doi: 10.1016/j.ajhg.2021.10.001. Epub 2021 Oct 25. PMID: 34699745
• Induced pluripotent stem cells-derived neurons from patients with Friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide. Sci Rep. 2019 Oct 10;9(1):14568.
  Georges P, Boza-Moran MG, Gide J, Pêche GA, Forêt B, Bayot A, Rustin P, Peschanski M, Martinat C, Aubry L.
  doi: 10.1038/s41598-019-49870-y. PMID: 31601825; PMCID: PMC6787055.

Collaborations:

• Malgorzata Rak, Inserm UMR 1141, Paris Diderot University, Robert Debré Pediatric Hospital, Paris, France
• Dr Cécile Delettre, Inserm U1051, Institut des Neurosciences de Montpellier, Montpellier, France
• Pr Timothy Barrett and Dr Malgorzata Zatyka, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
• Dr Patrick Yu Wai Man, Cambridge Centre for Brain Repair, University of Cambridge, UK
• Dr Eric Chevet, Inserm U1242, “Chemistry, Oncogenesis, stress, Signaling” (COSS), Rennes University, France