Progressive oxidative damage in the central nervous system of a murine model for juvenile Batten disease.

Oxidative damage is a known contributor to the pathogenesis of neurodegenerative diseases. Juvenile Batten disease is a progressive neurodegenerative disorder of childhood that results from mutation in Cln3. We have performed an initial characterization of the oxidative burden throughout the CNS in a Cln3(-/-) mouse model for juvenile Batten disease. A survey of multiple regions of the Cln3(-/-) mouse brain revealed a specific reduction of total glutathione, a tripeptide antioxidant molecule, in the cerebellum. Further analysis revealed an increase in protein oxidation not only in the cerebellum but also in the thalamus and primary motor cortex. Additionally, the thalamus was found to have an increase in the amount of a potent antioxidant enzyme, manganese superoxide dismutase (MnSOD), which may be in response to an increase in deleterious superoxide radicals. Colocalization studies indicate that microglia are localized directly adjacent to neurons expressing MnSOD, indicating that microglial activation may be related to the observed oxidative damage. This study helps to provide an initial measure of regions within the CNS of Cln3(-/-) mice that are specifically affected by the loss of CLN3 function and may serve to identify at the neuroanatomical level, the sequence of events that plays a role in the pathogenesis and clinical course of juvenile Batten disease.