Many questions still remain to be answered. One of the most important issues is how the disease progresses. Neuropathological studies implicate a spread of α-synuclein aggregate pathology [
13] because in early stages the pathological changes are restricted to certain areas that are constantly involved in later stages. These studies, however, are of limited use here because they assume Lewy bodies, rather than synaptic aggregates, to be an equivalent for the spread of pathology. The pattern of spread shows some parallels to prion diseases, although an infectivity of α-synuclein aggregates has not yet been shown. In prion diseases a trans-synaptic spread is evident [
95]. This pathway can easily be explained because the physiological prion protein is anchored at the outer surface of nerve cells and lymphocytes, and prion aggregates can be found extra- as well as intracellularly. In contrast, α-synuclein is a cytoplasmatic protein. The mode of spread is an actual matter of debate. Recent findings that α-synuclein pathology spreads to implanted grafts, focused research efforts on this topic. In three autopsy studies of patients who received transplants of foetal mesencephalic neurons 11–14 years earlier, Lewy body-like inclusions reacting with antibodies against α-synuclein were detected [
71,
72,
86]. These findings suggest that α-synuclein aggregation may spread from host to graft. The Lewy body-like pathology in grafted neurons does not necessarily mean their functional impairment. Our findings of synaptic α-synuclein pathology, although not yet shown in grafted neurons, may be one step towards explaining the graft pathology because the integration of grafts by synaptic contacts was demonstrated [
73], and a trans-synaptic spread is one possible explanation. Oligomeres of α-synuclein have been shown to be released from cultured cells by exocytosis [
83], and can be taken up via endocytosis [
84]. Recently a neuron-to-neuron spread of α-synuclein pathology was shown in a cell culture model using adenovirus-mediated α-synuclein overexpression. Additionally, a neuron-to-neuron spread was demonstrated using cortical neural stem cells that were implanted into α-synuclein transgenic mice [
27]. Other experiments have shown evidence that the pathological conformation of α-synuclein may act as a seed for forming aggregates in target cells [
92]. For β-amyloid [
102] and tau [
21] seeding effects have been shown to induce the aggregation of the respective protein in transgenic animal models. Interestingly, an induction of α-synuclein aggregates into the enteric nervous system by oral application of rotenone, which causes non-detectable levels of the toxin in blood or brain, was followed by a spread of α-synuclein pathology to the dorsal motor nucleus of the vagus, the intermediolateral nucleus in the spinal cord and the substantia nigra [
111]. With these recent findings, a trans-synaptic spread of α-synuclein pathology seems to be a more likely explanation for the propagation of the disease than alternative explanations such as inflammatory processes, oxidative stress or loss of neurotrophic support [
14]. The latter aspects may be more of interest for explaining the initiation of the α-synuclein aggregation. They may also make cells vulnerable to amplify aggregates.