Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis

  • Irene Lopez-Fabuel (Geteilte/r Erstautor/in)
  • Marina Garcia-Macia (Geteilte/r Erstautor/in)
  • Costantina Buondelmonte
  • Olga Burmistrova
  • Nicolo Bonora
  • Paula Alonso-Batan
  • Brenda Morant-Ferrando
  • Carlos Vicente-Gutierrez
  • Daniel Jimenez-Blasco
  • Ruben Quintana-Cabrera
  • Emilio Fernandez
  • Jordi Llop
  • Pedro Ramos-Cabrer
  • Aseel Sharaireh
  • Marta Guevara-Ferrer
  • Lorna Fitzpatrick
  • Christopher D Thompton
  • Tristan R McKay
  • Stephan Storch
  • Diego L Medina
  • Sara E Mole
  • Peter O Fedichev
  • Angeles Almeida
  • Juan P Bolaños

Abstract

CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage neurodegenerative disease highly prevalent in children. CLN7/MFSD8 gene encodes a lysosomal membrane glycoprotein, but the biochemical processes affected by CLN7-loss of function are unexplored thus preventing development of potential treatments. Here, we found, in the Cln7∆ex2 mouse model of CLN7 disease, that failure in autophagy causes accumulation of structurally and bioenergetically impaired neuronal mitochondria. In vivo genetic approach reveals elevated mitochondrial reactive oxygen species (mROS) in Cln7∆ex2 neurons that mediates glycolytic enzyme PFKFB3 activation and contributes to CLN7 pathogenesis. Mechanistically, mROS sustains a signaling cascade leading to protein stabilization of PFKFB3, normally unstable in healthy neurons. Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks. Thus, aberrant upregulation of the glycolytic enzyme PFKFB3 in neurons may contribute to CLN7 pathogenesis and targeting PFKFB3 could alleviate this and other lysosomal storage diseases.

Bibliografische Daten

OriginalspracheEnglisch
ISSN2041-1723
DOIs
StatusVeröffentlicht - 27.01.2022

Anmerkungen des Dekanats

© 2022. The Author(s).

PubMed 35087090