Huntington Disease (HD) is an autosomal dominant neurodegenerative disease caused by an expansion of a CAG trinucleotide repeat tract in the huntingtin (HTT) gene. This CAG tract expansion causes production of mutant HTT (mtHTT) protein, which misfolds and forms inclusions in the brain that accumulate with age. Misfolded mtHTT aggregates have been linked with increased cell death in neuron cell culture, leading to speculation that mtHTT aggregates cause cell death. However, there are mouse lines that have robust mtHTT inclusion deposition, but no HD-like signs or neurodegeneration. Furthermore, neuronal HD cultured cells with inclusions were found to be less likely to die compared to those with no inclusions. These findings indicate that mtHTT inclusions may play a neuroprotective role in HD by sequestering a toxic soluble form. Cell cultures show increased levels of stress response proteins when oligomeric mtHTT levels are elevated, indicating that oligomers may be the toxic species driving disease pathogenesis. Our lab has recently shown that inducing age-related changes in HD neurons induces oligomer formation. This finding suggests that there is a potential link between biological age and mtHTT misfolding. I am investigating this relationship by assessing mtHTT aggregation in the brains of HD model mice that have undergone anti-aging therapy using EM48, an antibody that recognizes misfolded mtHTT. The results of this study may provide further insight into the relationship between biological age and accumulation of misfolded mtHTT protein. If we find a relationship between biological age and mtHTT misfolding that can be therapeutically modulated, this may provide new insight into the ‘toxic species’ of mtHTT and would have implications for strategies aimed at reducing its levels. No effects of ‘young blood’ (YB) therapy were observed in this study. But due to limitations in the study, a conclusion on the effect of YB treatment will require further work, including optimization of image processing and processing of a greater number of animals.
Southwell, Amber L.
Bachelor of Science (B.S.)
College of Medicine
Burnett School of Biomedical Sciences
Biomedical Sciences; Neuroscience
Kesineni, Ratnesh, "Investigating the Relationship Between Biological Age and Mutant Huntingtin Misfolding" (2022). Honors Undergraduate Theses. 1160.