UC Riverside

Despite years of research, little is known about the specific cause of Parkinson's disease (PD), though genetic and environmental factors have been implicated. Evidence suggests that microtubule disruption may be involved; however this mechanism is not yet fully elucidated, and factors implicated in PD have not been conclusively related to microtubule function. This is the framework of this thesis.

We have expanded on a suggested PD cascade involving microtubule disruption triggering oxidization of dopamine, production of reactive oxygen species (ROS), aggregation of alpha-synuclein, and death of neuronal cells. We have provided computational and relational evidence demonstrating how factors implicated in PD may relate to microtubule disruption and reactive oxygen species (ROS). We selected 6 potentially PD-related compounds: rotenone, MPTP/MPP+, toluene, saccharin, and aspartame, and compared them to 4 tubulin inhibitors: colchicine, vinblastine, soblidotin, and taxol; identifying ~62% chemical similarity between rotenone and colchicine and ~78% similarity between aspartame and soblidotin. We performed molecular docking calculations for the potentially PD-related compounds at the binding sites of the tubulin inhibitors on tubulin dimers and found that all potentially PD-related molecules demonstrated lowest (strongest) binding affinities on the colchicine site of tubulin. Rotenone and aspartame demonstrated significant binding affinities of 10.7 and -8.7 kcal/mole, comparable to affinities of compounds on their known receptors (-15.0 to -9.2 kcal/mole).

As compounds would need to enter the bloodstream and cross the blood-brain barrier (BBB) to enact damage that could trigger PD, we illustrated that all potentially PD-related compounds evaluated meet criteria for potential to cross the BBB, and that all but one (aspartame) have been proven to enter the bloodstream. We hypothesized that aspartame, believed to not enter the bloodstream after digestion, may potentially be absorbed sublingually. We compared aspartame to known sublingual drugs and noted comparable logP and molecular weight values.

Lastly, we demonstrated via molecular docking probable methods of aggregation of alpha synuclein (á-syn) fibrils and probable mechanisms of two á-syn aggregation inhibitors, curcumin and geldanamycin. We have thus provided a collective body of evidence to help substantiate the hypothesis that PD may be triggered by tubulin inhibition leading to excessive ROS production, triggering a PD cascade.