Parkinson’s Disease, Alpha-Synucleinand Nanopore Analysis

Parkinson’s disease (PD) is caused by the death of dopamine producing neurons which leads to tremors and slowness of movement. The primary pathological event appears to be the misfolding and subsequent aggregation of α-synuclein (AS) which is an intrinsically disordered protein (IDP) of 140 amino acids. As with other IDPs, AS is difficult to study by conventional techniques because of its propensity to aggregate and its ability to adopt a number of different conformations.

Nanopore analysis is a single molecule technique which can interrogate the conformation of proteins at low concentrations in real time. Here I will demonstrate its application to understanding the interaction of drugs with α-synuclein. For example, methamphetamine causes compaction of AS whereas nicotine and caffeine prevent aggregation. It is, perhaps no coincidence that crack users have a higher incidence of PD whereas it is reduced in coffee drinkers and smokers. In the long term, I intend to use nanopore analysis to find drugs which bind tightly to AS and, therefore, will prevent the progression of the disease.