Progressive rod bipolar cell loss, ubiquitin accumulation, and subretinal drusenoid deposits in Cln3Δex7/8 mice: New insights into juvenile neuronal ceroid lipofuscinosis pathogenesis.

Juvenile neuronal ceroid lipofuscinosis (JNCL) is a rare neurodegenerative disorder caused by mutations in the CLN3 gene and characterized by early vision loss and a progressive neurological decline. To characterize the progression of retinal pathology, we conducted a 15-month study using the Cln3Δex7/8 mouse model which carries the most common causative mutation of JNCL. Retinal function was assessed every three months from the age of 3-15 months using electroretinography (ERG), optical coherence tomography (OCT), fundus imaging, and immunohistochemistry. OCT and fundus imaging in the Cln3Δex7/8 mice revealed a progressive thinning of the inner nuclear layer (INL) and an accumulation of subretinal drusenoid deposits. We detected a progressive loss of rod bipolar cells (RBCs) with immunofluorescence staining which was accompanied by ubiquitin-positive punctae, indicative of a potential role of the ubiquitin-proteasome system (UPS) in the selective loss of RBCs and the associated inner retinal dysfunction. Furthermore, late-stage immune cell activity was observed in the subretinal space of the Cln3Δex7/8 mice. ERG measurements confirmed previous findings of a predominant inner retinal dysfunction and revealed also a more pronounced photoreceptor impairment, as well as an earlier onset of retinal dysfunction than previously reported. These findings provide new insights into the pathological features of retinal degeneration in Cln3Δex7/8 mice, including subretinal drusenoid deposits, tubular subretinal fluid, and ubiquitin accumulation as well as a better overview of the rate of the degeneration process, thus expanding our understanding of JNCL pathogenesis.