Aberrant upregulation of glycolysis mediates CLN7 neuronal ceroid lipofuscinosis
| Autor: | García-Macia, Marina, López-Fabuel, Irene, Buondelmonte, Constantina, Burmistrova, Olga, Bonora, Nicoló, Morant Ferrando, Brenda, Alonso-Batán, Paula, Vicente-Gutiérrez, Carlos, Jimenez-Blasco, Daniel, Quintana-Cabrera, Ruben, Fernández, Emilio, McKay, Tristan R., Storch, Stephan, Medina, Diego L., Mole, Sara E, Fedichev, Peter O., Almeida, Angeles, Bolaños, Juan P. |
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| Přispěvatelé: | Agencia Estatal de Investigación (España) |
| Rok vydání: | 2021 |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | Resumen del trabajo presentado en el 43rd Annual Meeting of the Spanish Society of Biochemistry & Molecular Biology, celebrado en Barcelona, del 19 al 22 de julio de 2021 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 the autophagy-lysosomal pathway causes accumulation of structurally and bioenergetically impaired neuronal mi- tochondria. In vivo genetic approach revealed elevated mitochondrial reactive oxygen species (mROS) in Cln7∆ex2 neurons that mediates glycolysis activation and contributes to CLN7 pathogenesis. Mechanistically, mROS sustains a signaling cascade leading to protein stabilization of PFK- FB3, a glycolytic-promoting enzyme normally unstable in healthy neurons. Pharmacological inhibition of PFKFB3 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectified key disease hallmarks. Thus, aberrant upregulation of neuronal glycolysis contributes to CLN7 patho-genesis and targeting PFKFB3 may alleviate this and other lysosomal storage diseases This work was funded by Agencia Estatal de Investigación (PID2019-105699RB-I00). |
| Databáze: | OpenAIRE |
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