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Variant late-infantile neuronal ceroid lipofuscinosis (vLINCL), caused by  CLN6  mutation, and juvenile neuronal ceroid lipofuscinosis (JNCL), caused by  CLN3  mutation, share clinical and pathological features, including lysosomal accumulation of mitochondrial ATP synthase subunit c, but the unrelated  CLN6  and  CLN3  genes may initiate disease via similar or distinct cellular processes. To gain insight into the NCL pathways, we established murine wild-type and Cb Cln6   nclf/nclf  cerebellar cells and compared them to wild-type and Cb Cln3   Δex7/8/Δex7/8  cerebellar cells. Cb Cln6   nclf/nclf  cells and Cb Cln3   Δex7/8/Δex7/8  cells both displayed abnormally elongated mitochondria and reduced cellular ATP levels and, as cells aged to confluence, exhibited accumulation of subunit c protein in Lamp 1-positive organelles. However, at sub-confluence, endoplasmic reticulum PDI immunostain was decreased only in Cb Cln6   nclf/nclf  cells, while fluid-phase endocytosis and LysoTracker® labeled vesicles were decreased in both Cb Cln6   nclf/nclf  and Cb Cln3   Δex7/8/Δex7/8  cells, though only the latter cells exhibited abnormal vesicle subcellular distribution. Furthermore, unbiased gene expression analyses revealed only partial overlap in the cerebellar cell genes and pathways that were altered by the  Cln3   Δex7/8  and  Cln6   nclf  mutations. Thus, these data support the hypothesis that  CLN6  and  CLN3  mutations trigger distinct processes that converge on a shared pathway, which is responsible for proper subunit c protein turnover and neuronal cell survival.

Distinct Early Molecular Responses to Mutations Causing vLINCL and JNCL Presage ATP Synthase Subunit C Accumulation in Cerebellar Cells