Mitochondrial ROS contribute to neuronal ceroid lipofuscinosis pathogenesis

Trabajo presentado al 20th Biennial Meeting of The Society for Free Radical Research International (SFRR-I) del 15 al 18 de marzo de forma virtualNeuronal ceroid lipofuscinoses (NCLs), known as Batten disease, are the most common of the rare neurodegenerative disorders in children. These disorders are grouped together based on clinical similarities and uniform neuropathological features, including accumulation of lipofuscin in lysosomes and widespread gliosis. CLN7 disease is one of these NCLs that present in late infancy and is caused by mutations in the CLN7/MFSD8 gene, which encodes a lysosomal membrane glycoprotein of unknown function, hence the biochemical processes affected by CLN7-loss of function are not understood. Here, we found in the Cln7Δex2 mouse model of CLN7 disease that failure in the autophagy-lysosomal pathway causes aberrant accumulation of reactive oxygen species (ROS)-producing brain mitochondria. Metabolic profile analysis of Cln7Δex2 neurons revealed a decrease in the basal oxygen consumption rate (OCR), ATP-linked and maximal OCR and proton leak, indicating bioenergetically impaired mitochondria. To assess the impact of ROS on CLN7 disease progression, Cln7Δex2 mice were crossed with mice expressing a mitochondrial-tagged form of catalase (mCAT) governed by a neuron-specific promoter (Cln7Δex2-CAMKIIaCre-mCAT). The increased mROS observed in Cln7Δex2 neurons was abolished in Cln7Δex2- CAMKIIaCre-mCAT neurons, verifying the efficacy of this approach. The brain mitochondrial swelling and mitochondrial cristae profile widening observed in Cln7Δex2 mice were abolished in Cln7Δex2-CAMKIIaCre-mCAT mice. Notably, Cln7Δex2 brain accumulation of subunit C-ATPase and lysosomal lipofuscin, as well as gliosis, which are hallmarks of the disease, were ameliorated in Cln7Δex2- CAMKIIaCre-mCAT mice. Altogether, these findings indicate that the generation of ROS by bioenergetically-impaired mitochondria in Cln7Δex2 neurons contributes to the histopathological symptoms of CLN7 disease