Jordy Sepulveda

Jordy Sepulveda

PI: Aaron Bowman, Ph.D , Department of Neurology

BDNF down-regulation in Huntington’s Disease mouse model upon Manganese exposure

Huntington’s disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene (HTT). Evidence suggests that environmental factors such as Manganese (Mn) exposure alter symptom age-of-onset. Mn dyshomeostasis in the brain has been reported in both cell and mouse HD models, suggesting an impairment in Mn absorption, metabolism or transport in HD. I postulate that Mn absorption and transport is altered in both liver and brain in HD and that Mn dyshomeostasis modifies signaling pathways regulating neuronal survival and proliferation. To investigate this hypothesis, I utilized 12-week old, YAC128Q male mice expressing mutant HTT as well as wild-type littermates. I exposed mice to a subcutaneous injection of 13.88mg/kg Mn or vehicle for 0hrs, 1hr, 4hrs, 24hrs, and 1 week prior to sacrifice. At sacrifice, the brain and liver were dissected and sectioned into 2 segments: one for RNA isolation and another to generate a cell lysate. I measured differences in gene (using qRT-PCR) and protein expression (using Western blots) of known Mn responsive proteins and transporters including BDNF. There was no difference in baseline mRNA expression of BDNF in the liver between WT and HD mice. WT BDNF transcript levels in the liver increase 3-fold immediately after Mn exposure (p<0.05) while BDNF levels in HD mice decrease after 4 hrs following Mn exposure in the liver (p<0.05). We found no differences in BDNF mRNA in the brain. These initial findings may suggest that HD mice transport Mn into the liver more slowly than WT mice.