In 2008, two autopsy studies of patients with PD who survived more than 10 years after receiving successful transplants of embryonic dopamine neurons to treat their disease observed that the surviving transplanted neurons had α-synuclein accumulation in typical Lewy bodies [
39],[
40]. The only way these neurons could have such pathology was by a propagating mechanism, a concept of transmission more commonly associated with prion diseases [
41]. It should be noted that Braak and colleagues had in 2003 proposed a transmissible mechanism for α-synuclein propagation based on observations that the disease seemed to start in the nose and/or gut and progress to invade the brain in a staged manner [
42],[
43]. A number of subsequent studies in animal and cell culture models have proven this concept of transmission of α-synuclein between neurons, showing that exogenous α-synucleininduces Lewy body pathology along neuroanatomical pathways in the brain (for example [
44]-[
48]). It should be noted that it is the conformation of the protein that is transmitted to endogenous protein residing within neurons, as in mouse models the aggregates from exogenous sources disappear in about a week with endogenous aggregates beginning around 3 months later [
49]. This observation suggests that a particular strain of α-synuclein is transmitted between neurons.
Consistent with the concept of different prion strains [
50], a number of studies have now identified and characterized different strains of α-synuclein. Strains made
in vivo exhibit fundamentally different properties, including the packing of their building blocks and growth and amplification properties, as well as their tropism, cellular binding and penetration properties and toxicity [
51],[
52]. These differences can be exaggerated by modifying the solution concentration, molecular crowding, agitation, temperature, pH and ionic strength [
53]. Exogenous factors that accelerate the
in vitro aggregation of α-synuclein include agrochemicals, polycations, histones, metal ions, glycosaminoglycans, sodium dodecyl sulfate and organic solvents, while factors that inhibit α-synuclein aggregation include small chemical compounds, heat shock proteins, PAMAM dendrimers, α-synuclein and α-synuclein, catecholamines, phospholipids, rifampicin, trehalose and oxidative modifications [
53]. The combination of different factors may impact on the strains of α-synuclein in different people and may explain some of the heterogeneity that is known both clinically and pathologically, and especially in the dynamics of the different types of Lewy body diseases [
54]. Morphological and structural differences have been noted in patients with Lewy bodies consistent with the concept of different α-synuclein strains - Lewy bodies in the brainstem are morphologically different from those in the cortex [
55], and conformationally different strains of α-synuclein have been identified from cortical tissue samples of patients with PD depending on the presence or absence of Alzheimer pathologies [
52].