When Edouard Brissaud noticed clinical similarities between pseudobulbar palsy and parkinsonism, he made the hypothesis that their lesions were located in similar regions, and identified the subthalamic nucleus and mesencephalon, more specifically, the locus niger as the “best guess”. He was guided by a previous report by Blocq and Marinesco (1893), which had indeed described a case of unilateral parkinsonian syndrome associated with a mesencephalic “tumor”, probably a tuberculoma. Friedrich Lewy, in his well-documented book Die Lehre Vom Tonus und der Bewegung (1923), illustrated multiple types of inclusions located in various brain nuclei. He thought the extrapyramidal syndrome was related to an imbalance between the action of the cerebellum (the destruction of which causes hypotonia) and of the striatum (the destruction of which causes hypertonia), and a tonus center was supposed to balance the two antagonist effects. He believed the center was located in the mesencephalon, but doubted it was the substantia nigra. Tretiakoff dubbed some of the inclusions described by Lewy as “Lewy bodies”. Scheller's group (at Stanford University) discovered, in 1988, a new synaptic protein in the electric organ of the torpedo fish and called it “synuclein” (“syn” for synapse, “nuclein” for nucleus). It was unexpected to find the synuclein gene implicated in cases of familial Parkinson's disease, and a surprise to discover that Lewy pathology was directly related to alpha-synuclein accumulation. Strong experimental evidence now suggests that misfolded alpha-synuclein acts like a prion, seeding misfolding of normal alpha-synuclein and spreading it along neuronal pathways.