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Quantification and Analysis of Epigenetic Regulation of Brain-Derived Neurotrophic Factor (BDNF) in Huntington’s Disease


Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that affects motor coordination and cognitive function. HD neuropathology is characterized by substantial loss of medium spiny neurons in the striatum. Brain derived neurotrophic factor (BDNF) plays fundamental roles in the survival and activity of neurons, including striatal cells that die in HD. Previous reports shown substantial alterations in BDNF levels in the brains of HD cases; however, limited studies have explored the changes in BDNF across clinical stages of HD and levels present in peripheral fluids. We hypothesized that BDNF is increasingly deregulated during HD progression, and could be detected in plasma and saliva. Moreover, we propose that changes in BDNF gene expression may result from alterations in epigenetic mechanisms, specifically aberrant DNA methylation at the BDNF promoter; as previously reported to occur in other neurodegenerative disorders. We optimized an ELISA to measure BDNF in patients in different HD clinical stages and control subjects. We found lower levels of BDNF in saliva from subjects with the HTT gene mutation, regardless of HD clinical disease status in comparison to non-carriers. No changes in BDNF were found in plasma. We also determined the methylation levels at BDNF promoter IV by pyrosequencing. We found CpG sites differentially methylated in subjects with the HTT gene mutation. In summary, our preliminary studies suggest that BDNF protein levels and promoter methylation patterns may be associated with the huntingtin mutation and although they may be potentially indicative of the carrier status, fail to predict HD clinical progression.

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