Mechanisms of alpha-synuclein action on neurotransmission: cell-autonomous and non-cell autonomous role

Abstract

Mutations and duplication/triplication of the alpha-synuclein (αSyn)-coding gene have been found to cause familial Parkinson's disease (PD), while genetic polymorphisms in the region controlling the expression level and stability of αSyn have been identified as risk factors for idiopathic PD, pointing to the importance of wild-type (wt) αSyn dosage in the disease. Evidence that αSyn is present in the cerebrospinal fluid and interstitial brain tissue and that healthy neuronal grafts transplanted into PD patients often degenerate suggests that extracellularly-released αSyn plays a role in triggering the neurodegenerative process. αSyn's role in neurotransmission has been shown in various cell culture models in which the protein was upregulated or deleted and in knock out and transgenic animal, with different results on αSyn's effect on synaptic vesicle pool size and mobilization, αSyn being proposed as a negative or positive regulator of neurotransmitter release. In this review, we discuss the effect of αSyn on pre- and post-synaptic compartments in terms of synaptic vesicle trafficking, calcium entry and channel activity, and we focus on the process of exocytosis and internalization of αSyn and on the spreading of αSyn-driven effects due to the presence of the protein in the extracellular milieu.

Keywords: alpha-synuclein; calcium entry; exo/endocytosis; lipid microdomains; non-cell autonomous.

Figure 1

Structure of the αSyn protein. The N-terminal domain (red) is composed of KTKEGV repeats where human missense mutations associated to familial PD have been found. The central hydrophobic core (purple) is called NAC domain and promote aggregation of the protein. The C-terminal domain (green) is the acidic tail that contains phosphorylation sites and the calcium binding site.

Figure 2

Mechanisms of αSyn release and internalization. αSyn can be released from healthy neurons by conventional exocytosis of vesicles or MVB, or through exosomes, or can pass the membrane with the help of an unknown carrier. αSyn can enter neurons by internalization in vesicles, or through pores formed into the membrane by αSyn oligomers, or by direct translocation across the plasma membrane.

Figure 3

Targets of extracellular αSyn. Extracellular soluble αSyn induces an increase in calcium entry by acting on the fluidity of the membrane or by activating N-type calcium channels that shift to cholesterol-poor domains of the membrane. Extracellular soluble αSyn clusters GRP78 at the plasma membrane, with ensuing activation of a pathway that leads to cofilin 1 phosphorylation.