This mutation results in a substantial decrease in mRNA expression and stability due to nonsense-mediated decay, and most likely the mutant, truncated protein is not expressed at all 5. The most common disease-causing mutation of the CLN3 gene is a 1.02 kb deletion, which removes exons 7 and 8 and creates a premature stop codon. The motor deterioration is accompanied by cognitive decline and patients die between 15 and 35 years of age 4. During the disease course, patients become blind, display motor coordination deficits and progressively lose their motor skills. CLN3 disease begins between 4 and 10 years of age with visual impairment and seizures. Expression analyses indicate that the CLN3/ Cln3 gene and CLN3 protein is ubiquitously expressed in various human and mouse tissues 1. The most common, juvenile onset form of Batten disease, CLN3 disease, is caused by mutations in CLN3 3, which encodes a lysosomal/endosomal transmembrane protein of unknown function. Batten disease predominately affects children with an estimated incidence of 1–2 in 50,000 live births in the US 2. Similar content being viewed by othersīatten disease, also known as neuronal ceroid lipofuscinoses, is a group of recessively inherited, fatal lysosomal storage disorders characterized by the intracellular accumulation of autofluorescent lipopigment and progressive neurodegeneration 1. These results indicate that acidified water may provide therapeutic benefit to CLN3 Batten disease patients, and that the pH of drinking water is a major environmental factor that strongly influences the results of murine behavioral and pathological studies. Since the gut microbiota can influence neurological functions, we examined it in our disease model and found that the gut microbiota of Cln3 −/− mice was markedly different from control mice, and acidified water differentially changed the gut microbiota composition in these mice. Interestingly, in control mice, acidified drinking water caused brain region-specific glial activation and significant changes in motor performance. Indeed, acidified water temporarily attenuated the motor deficits, had beneficial effects on behavioral parameters and prevented microglial activation in the brain of Cln3 −/− mice. Here we investigated if acidified water administered from postnatal day 21 has therapeutic benefits in Cln3 −/− mice. When mice received acidified drinking water (pH 2.5–2.9) instead of normal tap water (pH 8.4) for several generations, the motor skills of Cln3 −/− mice normalized to control levels, indicating a disease-modifying effect of acidified water. The Cln3 −/− mouse model displays characteristic features of the human disease including motor deficits. CLN3 mutations cause the fatal neurodegenerative disorder, CLN3 Batten disease.
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