Abstract
Huntington’s disease (HD) is one of many neurodegenerative diseases characterized by loss of motor control and cognitive abilities gradually worsening over time. The onset of the disease is due to a mutation in the gene that codes for huntingtin protein. This mutant form of huntingtin misfolds to form aggregates that accumulate in neurons, especially in cell nuclei. It has been previously believed that these aggregates interfere with cell function and causes cell toxicity that leads to cell death. Other controversial views propose that these aggregates are serving as a defense mechanism in response to cell toxicity due to the presence of mutant huntingtin protein. The formation of these aggregates is dependent on the length of the CAG repeats coding for glutamine on the N-terminus of the huntingtin protein. The longer polyQ regions tend to form anti-parallel β-sheets consisting of hydrogen bonds between the main and side chain amines. The adjacent helical polyproline (polyP) region contributes to stabilization of the polyQ region by suppressing β-sheet formation. We are designing multivalent ligand scaffolds using ring-opening metathesis polymerization (ROMP) to target these areas on huntingtin protein to examine the effects on aggregation. Block co-polymers of different lengths displaying glutamine and tryptophan functionalities selected to interact with the polyQ and polyP regions are explored to target the protein. We hypothesize that block displays of functionality will bind better than random displays of functionality. The shorter-length polymers are hypothesized to inhibit aggregation while the longer-length polymers are hypothesized to induce aggregation based on the ability to bind multiple copies of the huntingtin protein. We designed block displays using orthogonal chemistry to synthesize polymers for use in biological analysis to understand the role of protein aggregation in HD.