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

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

This work was funded by Agencia Estatal de Investigación (PID2019-105699RB-I00).

Peer reviewed