Autophagy and mitophagy in the CLN8mnd mouse, a model of childhood neurodegenerative diseases

The autophagy is the major degradation system of the cell for long-lived proteins and organelles. Dysfunction of autophagy has been linked to several neurodegenerative disorders that are associated with an accumulation of misfolded protein aggregates, but also to the lysosomal impairment in lysosomal storage diseases. Recently, a selective mitochondrial quality control has been suggested to require a specific form of autophagy, termed "mitophagy". The CLN8mnd mouse is a naturallyoccurring model of the CLN8-associated late-infantile forms of the neuronal ceroid lipofuscinoses (NCLs), that are neurodegenerative diseases characterized by epilepsy, progressive motor and cognitive decline, blindness, and by lysosomal lipopigment accumulation. The pathomechanisms of NCLs are still unknown. The CLN8mnd mouse carries a frameshift mutation in the CLN8 gene encoding a truncated protein at the endoplasmic reticulum (ER). The typical autofluorescent lipopigment accumulation of NCLs appears before mnd symptoms and contains lipofuscin-ceroid and the mitochondrial ATPase subunit C, which is suggestive of defective mitochondria. Previously, we observed oxidative and ER stresses and inflammation occurring over the mnd disease (Guarneri et al. 2004;Galizzi et al., 2011). Here, we investigated on autophagic hallmarks in the CLN8mnd cerebellum at presymptomatic and symptomatic states, and especially focused the Parkin, BNIP3, NIX and p62/SQSTM1 that selectively promote mitochondrial clearance. Our results suggest that both macro- and selective-autophagy are primed, however they also indicate a defective autophagosome maturation likely contributing to disease progression. Consistently, we recently found that the wild-type CLN8 interacts with GATE-16, BNIP3 and NIX (Passantino et al. SINS Congress 2012). Therefore, the mutated CLN8 might interfere with either GATE-16 function in sealing of late autophagosomes or GATE-16-BNIP3-NIX-interconnected function in mitophagy.