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

Autor(es):Mostrar menos -

Zatyka, Malgorzata ; Rosenstock, Tatiana R. ; Sun, Congxin ; Palhegyi, Adina M. ; Hughes, Georgina W. ; Lara-Reyna, Samuel ; Astuti, Dewi ; di Maio, Alessandro ; Sciauvaud, Axel ; Korsgen, Miriam E. ; Stanulovic, Vesna ; Kocak, Gamze ; Rak, Malgorzata ; Pourtoy-Brasselet, Sandra ; Winter, Katherine ; Varga, Thiago ; Jarrige, Margot ; Polveche, Helene ; Correia, Joao ; Frickel, Eva-Maria ; Hoogenkamp, Maarten ; Ward, Douglas G. ; Aubry, Laetitia ; Barrett, Timothy ; Sarkar, Sovan

• Tipo de documento: Artigo Científico
• Fonte: STEM CELL REPORTS; v. 18, n. 5, p. 17-pg., 2023-05-09.

Resumo

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. Here we demonstrate mitochondrial dysfunction in human induced pluripotent stem cell-derived neuronal cells of WS patients. VDAC1 is identified to interact with WFS1, whereas loss of this interaction in WS cells could compromise mitochondrial function. Restoring WFS1 levels in WS cells reinstates WFS1-VDAC1 interaction, which correlates with an increase in MAMs and mitochondrial network that could positively affect mitochondrial function. Genetic rescue by WFS1 overexpression or pharmacological agents modulating mito-chondrial function improves the viability and bioenergetics of WS neurons. Our data implicate a role of WFS1 in regulating mitochon-drial functionality and highlight a therapeutic intervention for WS and related rare diseases with mitochondrial defects. (AU)

• Processo FAPESP: 15/02041-1 - O papel das lisinas(K)-deacetilases para a neuroproteção de desordens mitocondriais: perspectivas de terapia epigenética para a esclerose lateral amiotrófica e esquizofrenia
• Beneficiário: Tatiana Rosado Rosenstock
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores