Distinct Early Molecular Responses to Mutations Causing vLINCL and JNCL Presage ATP Synthase Subunit C Accumulation in Cerebellar Cells
Copyright policy )Distinct Early Molecular Responses to Mutations Causing vLINCL and JNCL Presage ATP Synthase Subunit C Accumulation in Cerebellar Cells
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 CbCln6(nclf/nclf) cerebellar cells and compared them to wild-type and CbCln3(Δex7/8/Δex7/8) cerebellar cells. CbCln6(nclf/nclf) cells and CbCln3(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 CbCln6(nclf/nclf) cells, while fluid-phase endocytosis and LysoTracker® labeled vesicles were decreased in both CbCln6(nclf/nclf) and CbCln3(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.
- Harvard University United States
- Massachusetts General Hospital United States
- Griffith University Australia
- MASSACHUSETTS GENERAL HOSPITAL
Cell Survival, Science, Biochemistry and Cell Biology not elsewhere classified, Mice, Transgenic, Mice, Neuronal Ceroid-Lipofuscinoses, Cerebellum, Animals, Cluster Analysis, Humans, Cells, Cultured, Neurons, Membrane Glycoproteins, Gene Expression Profiling, Q, R, Membrane Proteins, Mitochondrial Proton-Translocating ATPases, Microarray Analysis, Mice, Inbred C57BL, Protein Subunits, Mutation, Medicine, Research Article, Molecular Chaperones, Signal Transduction
Cell Survival, Science, Biochemistry and Cell Biology not elsewhere classified, Mice, Transgenic, Mice, Neuronal Ceroid-Lipofuscinoses, Cerebellum, Animals, Cluster Analysis, Humans, Cells, Cultured, Neurons, Membrane Glycoproteins, Gene Expression Profiling, Q, R, Membrane Proteins, Mitochondrial Proton-Translocating ATPases, Microarray Analysis, Mice, Inbred C57BL, Protein Subunits, Mutation, Medicine, Research Article, Molecular Chaperones, Signal Transduction
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