title: Lithium rescues the impaired autophagy process in CbCln3(Δex7/8/Δex7/8) cerebellar cells and reduces neuronal vulnerability to cell death via IMPase inhibition.
abstract: Juvenile neuronal ceroid lipofuscinosis (Batten disease) is a neurodegenerative disorder caused by mutation in CLN3. Defective autophagy and concomitant accumulation of autofluorescence enriched with mitochondrial ATP synthase subunit c were previously discovered in Cln3 mutant knock-in mice. In this study, we show that treatment with lithium reduces numbers of LC3-positive autophagosomes and accumulation of LC3-II in Cln3 mutant knock-in cerebellar cells (CbCln3(Δex7/8/Δex7/8) ). Lithium, an inhibitor of GSK3 and IMPase, reduces the accumulation of mitochondrial ATP synthase subunit c and autofluorescence in CbCln3(Δex7/8/Δex7/8) cells, and mitigates the abnormal subcellular distribution of acidic vesicles in the cells. L690,330, an IMPase inhibitor, is as effective as lithium in restoring autophagy in CbCln3(Δex7/8/Δex7/8) cells. Moreover, lithium or down-regulation of IMPase expression protects CbCln3(Δex7/8/Δex7/8) cells from cell death induced by amino acid deprivation. These results suggest that lithium overcomes the autophagic defect in CbCln3(Δex7/8/Δex7/8) cerebellar cells probably through IMPase, thereby reducing their vulnerability to cell death.
authors.affiliation: Creative Research Initiative (CRI)-Acceleration Research Laboratory, School of Biological Science/Bio-MAX Institute, Seoul National University, Seoul, Korea.
authors.forename: Jae-Woong
authors.initials: JW
authors.lastname: Chang
authors.forename: Hyunwoo
authors.initials: H
authors.lastname: Choi
authors.forename: Susan L
authors.initials: SL
authors.lastname: Cotman
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055879:Gene Knock-In Techniques; D008094:Lithium / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
chemical_list: C102229:CLN3 protein, mouse; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D008094:Lithium; D015720:5'-Nucleotidase