A biophysical perspective on the unexplored mechanisms driving Parkinson’s disease by amphetamine-like stimulants

摘要

Epidemiologicalstudies havereported an increased risk ofParkinson’s disease(PD) development in amphetamine-typestimulant users during their lifetime(Garwood etal., 2006; Rumpfetal., 2017). Protein inclusions mainly composed ofmisfolded and aggregated α-synuclein arethe pathological hallmark ofPDand other disorders known as synucleinopathies. Molecular studies presentevidencethatamphetamine upregulates αsynuclein synthesis in substantia nigra. Theincrement of α-synuclein levels promotes itsaggregation and amyloid fibrilformation, increasing reactive oxygen species (ROS),and consequently dopamine oxidation (Wang and Witt, 2014), known to betoxicfor dopaminergic neurons involved in motor function and limbic-motor integration. Over the years, these damaged cells losetheir functionality and may die precociously, depleting the reserve of neuralcells necessary for the normal neurologicalfunctionwhich contributes to the onset ofPD, when acritical number ofcellsarelost (Garwood etal., 2006). Therefore, the use ofamphetamine-typestimulants may beatriggerevent in the development ofPDand parkinsonism, in conjugation to other risk factors thata given individualmay hold. Despitetheevidence,a previous study suggests that thereis notenough datato corroboratetheloss of dopamine neurons dueto human amphetamine-typestimulantexposure,and consequently its implication in the PD development (Kish etal., 2017). Thus,elucidating the mechanisms underlying amphetamine-typestimulant influence on PDmay contributeto better knowledgeabout therisk factors for the onset ofthis disease by thesesubstancesand adoptsocial policies to prevent futurecases. The present perspective highlights the uncharted spots ofthe molecular mechanisms of α-synuclein aggregation pathwaysand howadditionalstudiesare necessary to understand therole ofamphetamine-likestimulantsas triggers ofPDby changing α-synuclein thermodynamicand kineticlandscape.