Novel insights in the pathophysiology of α-synuclein dysregulation on D2 receptor activity contributing to the vulnerability of dopamine neurons

Abstract

Pathophysiological damages and loss of function of dopamine neurons precedes their demise and contributes to the early phases of Parkinson’s disease. The presence of aberrant intercellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson’s disease. We employed multiple complementary approaches in molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein levels alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission prior to neuronal demise. These studies demonstrate that α-synuclein dysregulation of D2 receptor autoinhibition contributes to the vulnerability of dopaminergic neurons, and that modulation thereof can ameliorate the resulting pathophysiology. These novel findings provide mechanistic insights in the insidious loss of dopaminergic function and neurons that characterize Parkinson’s disease progression with significant therapeutic implications.