Mitochondrial collapse links PFKFB3-promoted glycolysis with CLN7/MFSD8 neuronal ceroid lipofuscinosis pathogenesis

The neuronal ceroid lipofuscinoses (NCLs) are a family of monogenic life-limiting pediatric neurodegenerative disorders collectively known as Batten disease1. Although genetically heterogeneous2, NCLs share several clinical symptoms and pathological hallmarks such as lysosomal accumulation of lipofuscin and astrogliosis2,3. CLN7 disease belongs to a group of NCLs that present in late infancy4-6 and, whereas CLN7/MFSD8 gene is known to encode a lysosomal membrane glycoprotein4,7-9, the biochemical processes affected by CLN7-loss of function are unexplored thus preventing development of potential treatments1,10. Here, we found in the Cln7{Delta}ex2 mouse model11 of CLN7 disease that failure in the autophagy-lysosomal pathway causes accumulation of structurally and bioenergetically impaired, reactive oxygen species (ROS)-producing neuronal mitochondria that contribute to CLN7 pathogenesis. Cln7{Delta}ex2 neurons exhibit a metabolic shift mediated by pro-glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3). PFKFB3 inhibition in Cln7{Delta}ex2 mice in vivo and in CLN7 patients-derived cells rectified key disease hallmarks. Thus, specifically targeting glycolysis may alleviate CLN7 pathogenesis.