The common neuropathological hallmarks in neurons and glia are microscopic proteinaceous inclusions, composed mainly of aggregated fibrillar alpha-synuclein . aSN is an abundant presynaptic protein in the brain. Its 140 amino-acid sequence is highly homologous across human, rat and mouse . Initially, aSN microscopic aggregates were postulated to play a key role in the pathophysiology of a-synucleinopathies. Neurotoxicity findings implicate aSN protofibrils, soluble aSN protein WZ-4002 EGFR/HER2 inhibitor complexes, posttranslationally modified forms of aSN , phosphorylated at serine 129 , as well as mono- and di-ubiquitinated aSN forms . In DLB brains more than 90% of the insoluble aSN is phosphorylated at Ser129 compared to about 4% phosphorylated at Ser129 in brains of normal individuals. Furthermore, Ser129 phosphorylated aSN is targeted to mono- and di-ubiquitination in a-synucleinopathy brains . Extensive phosphorylation at Ser129 and/or its mono- and di-ubiquitination are critical events in the pathophysiology of aSN. However, direct experimental evidence supporting this notion is lacking and it is still debated whether these molecular forms of aSN are on the critical pathophysiological path rather than representing molecular epiphenomena of the disease process. As multiple toxic mechanism have been proposed for aSN, it is important to determine which of its molecular forms are on the critical pathophysiological path. One main hypothesis of aSN toxicity is based on its capability to form toxic oligomers. Familial forms of Parkinson��s disease possess mutant forms of aSN A53T and A30P that form oligomers more rapidly than wildtype aSN. In idiopathic forms of a-synucleinopathies that lack heritable aSN mutations, it is speculated that compromised handling of aSN and/or specifically modified forms are hampering aSN catabolism as well as that of other proteins. Oxidative damage of aSN could change aSN into toxic forms that trigger such a pathophysiological cascade . It is unclear how critical to the disease process are some of the differences in aSN amino-acid sequence between human, rat and mouse. There is no solid evidence for endogenous mouse aSN coaggregating with human aSN expressed in transgenic rodent models .