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

Irene Lopez-Fabuel (), Marina Garcia-Macia, 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 and Juan P. Bolaños ()
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Irene Lopez-Fabuel: Universidad de Salamanca, CSIC
Marina Garcia-Macia: Universidad de Salamanca, CSIC
Costantina Buondelmonte: Universidad de Salamanca, CSIC
Olga Burmistrova: Gero Discovery LLC
Nicolo Bonora: Universidad de Salamanca, CSIC
Paula Alonso-Batan: Universidad de Salamanca, CSIC
Brenda Morant-Ferrando: Universidad de Salamanca, CSIC
Carlos Vicente-Gutierrez: Universidad de Salamanca, CSIC
Daniel Jimenez-Blasco: Universidad de Salamanca, CSIC
Ruben Quintana-Cabrera: Universidad de Salamanca, CSIC
Emilio Fernandez: Universidad de Salamanca, CSIC
Jordi Llop: Basque Research and Technology Alliance (BRTA)
Pedro Ramos-Cabrer: Basque Research and Technology Alliance (BRTA)
Aseel Sharaireh: Manchester Metropolitan University
Marta Guevara-Ferrer: Manchester Metropolitan University
Lorna Fitzpatrick: Manchester Metropolitan University
Christopher D. Thompton: Manchester Metropolitan University
Tristan R. McKay: Manchester Metropolitan University
Stephan Storch: University Medical Center Hamburg-Eppendorf
Diego L. Medina: Telethon Institute of Genetics and Medicine (TIGEM), High Content Screening Facility
Sara E. Mole: University College London
Peter O. Fedichev: Gero Discovery LLC
Angeles Almeida: Universidad de Salamanca, CSIC
Juan P. Bolaños: Universidad de Salamanca, CSIC

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28191-1

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