BPS2026 – N-n-propylnorapomorphine as a multifaceted modulator of Huntington aggregation and membrane binding

Huntington’s disease (HD) is a genetic neurodegenerative disorder caused by an expanded polyglutamine (polyQ) tract near the N terminus of the huntingtin protein (HTT). This polyQ expansion triggers the ordered aggregation of HTT into amyloid fibrils, which accumulate as inclusions in the brains of HD patients. The length of the polyQ tract is a significant indicator of both aggregation rates and illness severity. This aggregation involves many distinct aggregate species, including oligomers, which exhibit different degrees of neurotoxicity. As a result, strategies to prevent aggregation have been extensively studied for potential therapeutic benefit. Importantly, HTT readily binds to and damages various membranes throughout cells. Therefore, inhibiting this HTT/lipid interaction could be an alternate tactic. As this demonstrates the multifaceted nature of HTT-associated toxicity, compounds that target these different features may prove to be particularly useful. Using a screen to discover compounds that block HTT/lipid interactions, N-n-propylnorapomorphine (NPA) was identified as a potential candidate. N-n-PropyInorapomorphine is an aporphine derivative dopamine agonist closely related to apomorphine. Using Thioflavin T and atomic force microscopy (AFM), NPA slows fibril formation. HTT oligomers formed in the presence of NPA initially swelled to larger sizes compared to the control; however, over time, these oligomers condensed to smaller sizes. When using AFM to track aggregate formation at the solid/liquid interface, NPA slowed HTT deposition and fibril formation. NPA also blocks the ability of HTT to bind and damage lipid membranes, as assessed by lipid binding assays and in solution AFM. While these in vitro experiments clearly demonstrate that NPA alters the aggregation and lipid interactions of mutant HTT, the impact on HD phenotype in vivo is still being evaluated. As such, NPA represents a potential multifaceted drug candidate that targets HTT aggregation, membrane binding, and dopamine activity.