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