Lithium rescues the impaired autophagy process in CbCln3 ^{δex7/8/δex7/8} cerebellar cells and reduces neuronal vulnerability to cell death via IMPase inhibition

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.