From α-synuclein to synaptic dysfunctions: new insights into the pathophysiology of Parkinson's disease

Alpha-synuclein is a natively unfolded protein playing a key role in the regulation of several neuronal synaptic functions in physiological and pathological conditions. Many studies, over the past years, have shown that it is actively involved in PD pathophysiology. Alpha-synuclein is integrated in a complex network of neuronal processes through the interaction with cytosolic and synaptic proteins. Hence, it is not the sole α-synuclein pathology but its effects on diverse protein partners and specific cellular pathways in the membrane and/or cytosolic districts such as endoplasmic reticulum/Golgi, axonal and synaptic compartments of dopaminergic neurons, that may cause the onset of neuronal cell dysfunction and degeneration which are among the key pathological features of the PD brain. Here we summarize a series of experimental data supporting that α-synuclein aggregation may induce dysfunction and degeneration of synapses via these multiple mechanisms. Taken together, these data add new insights into the complex mechanisms underlying synaptic derangement in PD and other α-synucleinopathies. This article is part of a Special Issue entitled: Brain Integration.