MassIVE MSV000091646

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

Description

WFS1 pull-down in HEK293 cells transfected with WFS1 expression plasmid. Precipitated proteins were separates into 13 fractions by SDS-PAGE, digested with trypsin and analyzed by LC-MS/MS. Samples P1-13 = pull-down with anti-WFS rabbit polyclonal (Cell Signaling Technologies #8749S), samples N14-26 = negative control (rabbit IgG). 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 MAMresident protein WFS1 causes Wolfram syndrome (WS), a rare early-onset neurodegenerative disease that has been linked to mitochondrial abnormalities. Here we demonstrated mitochondrial dysfunction in human induced pluripotent stem cellderived neuronal cells of WS patients. VDAC1 was identified to interact with WFS1, whereas loss of this interaction in WS cells could compromise mitochondrial function. Restoring WFS1 levels in WS cells reinstated WFS1-VDAC1 interaction, which correlated with increase in MAMs and mitochondrial network that could positively affect mitochondrial function. Genetic rescue by WFS1 overexpression 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 intervention for WS and related rare diseases with mitochondrial defects. [doi:10.25345/C5QR4P139] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: WFS1, Wolframin, Wolfram-syndrome, mitochondria

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Principal Investigators:
(in alphabetical order)
Sovan Sarkar, University of Birmingham, United Kingdom
Submitting User: Doug
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