Synucleins are small naturally unfolded proteins involved in neurodegenerative diseases and cancer. sequence KTKEGV. Despite their general sequence similarity, the known family show variations within their biochemical properties, playing a number of roles outside and inside from the cell. Because the discovery from the first relation 30 years back synucleins attract constant interest of researchers for their uncommon properties and association with human being diseases . Members of the synuclein family are readily secreted  and circulate between cells. Several hypotheses including endocytosis, exosomes [2,3,4,5], and tunneling nanotube formation  were generated to explain synuclein secretion. However, none of them was completely satisfactory and did not explain all the unusual properties of -synuclein. -Synuclein may be released into extracellular space as a result of oxidative stress  and other stress conditions. Interestingly, synucleins do not contain signal peptides at the N-termini and therefore use unconventional mechanism of secretion [8,9]. Moreover, -synuclein spreads out in a prion-like manner between neurons and other cell types, contributing to the dissemination of the pathology. Synucleins are relatively small proteins (127C140 amino acids for human proteins), but the tiny size cannot explain their secretion, cell-to-cell-spreading and propagation, since aggregated forms of the protein are also circulating between cells. These forms include large misfolded preformed fibrils (PFF) of -synuclein with 200 nm in size or bigger . This enigmatic mechanism draws a lot of attention from researchers, since these proteins not only initiate pathology, but also contribute to its propagation. As a result, they are attractive targets for the pharmacological interventions for neurodegenerative diseases. Another unresolved question concerning -synuclein biochemistry is what is a trigger that initiates the conversion of this protein from its normal physiological functions to a pathological role, associated with neurotoxicity and prion-like properties? Molecular mechanisms TGX-221 underlying -synuclein secretion, intercellular propagation, as well as its ability to acquire prion-like properties and accompanying pathological functions remain obscure. In recent years, the focus of synucleins research is shifting from intracellular to extracellular forms of these proteins and their impact on intracellular processes of adjacent cells. A number of recent studies suggests that extracellular -synuclein acts as a specific ligand for cell surface receptors [11,12,13,14]. Oligomeric -synuclein binding to cell surface receptors induces the transmission of signal into cells and causes a variety of biochemical and physiological reactions, including Ca2+ dysregulation , synaptic dysfunction, neurodegeneration, cognitive deficit, etc. -synuclein has promiscuous partners, and many synuclein-interacting intracellular proteins have been identified before . Recent results point to an important role of -synuclein binding to cellular surface receptors which transmit signals affecting intracellular processes. One of TGX-221 such interacting protein is a cellular prion protein (PrPC). -synuclein in addition to possessing prion-like properties itself [17,18] interacts with PrPC [11 directly,12,13]. This assistance facilitates the transfer of -synuclein TGX-221 between cells . Furthermore, such discussion causes synaptic dysfunction with a signaling cascade performing through phosphorylation of Fyn kinase and activation from the N-methyl-D-aspartate receptor [11,12,13,14]. Evidently, prPC and -synuclein usually do not type a good complicated, but get excited about short-term transitory interaction that alters -synuclein properties and conformation. An important outcome of -synuclein-PrPC binding may be the induction of cofilin/actin rods development , changing actin dynamics and leading Rabbit Polyclonal to ITCH (phospho-Tyr420) to rearrangements of cytoskeleton (Shape 1). Cofilin-actin bundles or rods shaped in axons and dendrites of pressured neurons could cause synaptic dysfunction and mediate cognitive deficits in dementias.