8th International Wolfram Symposium Presentation by Dr Malgorzata Zatyka – Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham. UK

Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome.

Abstract: Mitochondrial dysfunction involving mitochondria-associated ER membrane (MAM) dysregulation is implicated in the pathogenesis of late-onset neurodegenerative diseases, but understanding is limited for rare early-onset conditions. Loss of the MAM resident protein WFS1 causes Wolfram syndrome (WS), a rare early-onset neurodegenerative disease that has been linked to mitochondrial abnormalities. However, contradictory reports on mitochondrial functionality in non-human or nonclinical cell models and lack of data in disease- affected settings have precluded biomedical exploitation.

Here we demonstrated mitochondrial dysfunction in human induced pluripotent stem cell-derived neuronal cells of WS patients. VDAC1 was identified to interact with WFS1, whereas loss of this interaction in WS cells could compromise mitochondrial function. Genetic rescue by WFS1 restoration or pharmacological agents modulating mitochondrial function improved the viability and bioenergetics of WS neurons. Our data implicate a role of WFS1 in regulating mitochondrial functionality and highlight a therapeutic target for WS and related rare diseases with mitochondrial defects.

Points noted:

·  Mitochondrial dysfunction and increased oxidative stress are seen in human induced PCS derived neuronal cells from WS patients.

·  Not all typical biochemical mitochondrial markers were seen in WS patient derived cells.

·  Treatment to rescue WSF1, rescued mitochondrial function and reduced cell death.

·  WSF1 interacts with VDAC1 and may regulate VDAC1 function formation.

·  Not yet assessed investigational compounds in this model to evaluate potential benefits.

Deafblind Awareness Week…did you know that a red and white cane indicates deafblindness!  White canes are commonly used by people who are visually impaired or blind. But if you see someone with a red and white striped cane, they are likely to be deafblind. Support the Snow Foundation today in honor of those who struggle with vision and hearing loss.  https://thesnowfoundation.org/donate/

Deafblind Awareness Week…It affects everyone differently, some might need to adjust the settings on their TV or turn up the volume on the phone, and others might need assistance dogs, canes and more formal care. But for anyone affected, everyday activities can be difficult and time consuming. Imagine trying to book a doctor’s appointment, meet a friend for coffee, or even make dinner if you can’t see or hear very well. Support the Snow Foundation today in honor of those who struggle with vision and hearing loss.  https://thesnowfoundation.org/donate/

This week is Deafblind Awareness week. Over 15 million people worldwide are estimated to be living with severe deafblindness. Support the Snow Foundation today in honor of those who struggle with vision and hearing loss. https://thesnowfoundation.org/donate/