This hypothesis has first

been proposed after observing that fetal mesencephalic cells grafted into the brain of PD patients 11–22 years earlier contained classical LB inclusions [54], [55] and [56]. This suggested that α-SYN could be transmitted from the affected host neurons to healthy transplanted neurons, where it recruited normal α-SYN to misfold. Other findings derived from tissue culture and transgenic animals demonstrated cell-to-cell transfer of α-SYN inducing pathological changes and cell death in the recipient [48] and [57]. Recently, Luk and co-workers demonstrated the widespread propagation of pathological α-SYN aggregates throughout anatomically connected regions of the CNS following brain injection of synthetic α-SYN fibrils into α-SYN transgenic or wild type Target Selective Inhibitor Library mouse nontransgenic mice [58]. They suggested a mechanistic link between α-SYN transmission and PD hallmarks as α- SYN

pathology resulted in the progressive loss of DA nigral neurons and a consecutive striatal dopamine depletion of sufficient magnitude to induce detectable motor deficits [59]. Accumulating evidence suggests that PD may indeed be a prion-like disorder and GSK126 nmr that α-SYN behaves like the protein prion (PrP), which underlies disorders such as Creutzfeld–Jakob disease or bovine spongiform encephalopathy. Both proteins share many similarities: (i) they can undergo an aberrant conformational change from a

native α-helix to a β-sheet conformation which Selleck Decitabine promotes their self-aggregation, (ii) their protein aggregates can act as “seeds” to recruit and promote the misfolding of wild-type proteins, (iii) their misfolded protein form is recognized to be toxic and induce neurodegeneration [60]. The transmission of LB pathology following a prion-like mechanism through anatomically linked neuronal network might explain the sequential and predictable topographical progression of PD observed by Braak and co-workers. The mechanisms by which intracellular protein aggregates can reach neighboring cells in the CNS are not clear, and may involve neuronal transmission by exocytosis and endocytosis as well as spreading throughout the nervous system via anterograde and retrograde transport. Among the many hypotheses surrounding PD etiology, environmental toxin exposure has been the most studied. The awareness of a relationship with PD was raised during the 1980s, when young individuals developed PD signs after an intake of designer drugs contaminated with 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), a substance similar to the herbicide paraquat [61]. MPTP was then demonstrated to selectively damage nigral neurons by blocking mitochondrial complex I [62]. Since then, many pesticides (i.e., rotenone), herbicides (i.e., paraquat) or insecticides were positively associated to PD risk [63].