Acidified drinking water improves motor function, prevents tremors and changes disease trajectory in Cln2R207X mice, a model of late infantile Batten disease

Abstract

Batten disease is a group of mostly pediatric neurodegenerative lysosomal storage disorders caused by mutations in the CLN1-14 genes. We have recently shown that acidified drinking water attenuated neuropathological changes and improved motor function in the Cln1^R151X and Cln3^-/- mouse models of infantile CLN1 and juvenile CLN3 diseases. Here we tested if acidified drinking water has beneficial effects in Cln2^R207X mice, a nonsense mutant model of late infantile CLN2 disease. Cln2^R207X mice have motor deficits, muscle weakness, develop tremors, and die prematurely between 4 and 6 months of age. Acidified water administered to Cln2^R207X male mice from postnatal day 21 significantly improved motor function, restored muscle strength and prevented tremors as measured at 3 months of age. Acidified drinking water also changed disease trajectory, slightly delaying the death of Cln2^R207X males and females. The gut microbiota compositions of Cln2^R207X and wild-type male mice were markedly different and acidified drinking water significantly altered the gut microbiota of Cln2^R207X mice. This suggests that gut bacteria might contribute to the beneficial effects of acidified drinking water. Our study demonstrates that drinking water is a major environmental factor that can alter disease phenotypes and disease progression in rodent disease models.