Infantile neuroaxonal dystrophy (INAD) is caused by recessive variants in PLA2G6 and is a lethal pediatric neurodegenerative disorder. Loss of the Drosophila homolog of PLA2G6, leads to ceramide accumulation, lysosome expansion, and mitochondrial defects. Here, we report that retromer function, ceramide metabolism, the endolysosomal pathway, and mitochondrial morphology are affected in INAD patient-derived neurons. We show that in INAD mouse models, the same features are affected in Purkinje cells, arguing that the neuropathological mechanisms are evolutionary conserved and that these features can be used as biomarkers. We tested 20 drugs that target these pathways and found that Ambroxol, Desipramine, Azoramide, and Genistein alleviate neurodegenerative phenotypes in INAD flies and INAD patient-derived neural progenitor cells. We also develop an AAV-based gene therapy approach that delays neurodegeneration and prolongs lifespan in an INAD mouse model.

Even during sustained attention, enhanced processing of attended stimuli waxes and wanes rhythmically, with periods of enhanced and relatively diminished visual processing (and subsequent target detection) alternating at 4 or 8 Hz in a sustained visual attention task. These alternating attentional states occur alongside alternating dynamical states, in which lateral intraparietal cortex (LIP), the frontal eye field (FEF), and the mediodorsal pulvinar (mdPul) exhibit different activity and functional connectivity at α, β and γ frequencies-rhythms associated with visual processing, working memory, and motor suppression. To assess whether and how these multiple interacting rhythms contribute to periodicity in attention, we propose a detailed computational model of FEF and LIP. When driven by θ-rhythmic inputs simulating experimentally-observed mdPul activity, this model reproduced the rhythmic dynamics and behavioral consequences of observed attentional states, revealing that the frequencies and mechanisms of the observed rhythms allow for peak sensitivity in visual target detection while maintaining functional flexibility.