Structure of parkin and a model of parkin-mediated ubiquitination and its substrates. In the top panel, the modular architecture of parkin is depicted, and the locations of the reported familial-associated disease-causing missense mutations are indicated. Disease-causing deletions, insertions, and frameshifts are not depicted (see text for details). The bottom panel shows a model of parkin-mediated ubiquitination and Lewy body formation. Parkin may play key roles in both ubiquitination and Lewy body formation in conjunction with the E1 ubiquitin-activating enzyme and the E2s UbcH7, UbcH8, UBC6, and UBC7. Nonglycosylated α-synuclein accumulates in Lewy bodies through mechanisms that are not clear, but it may inhibit (–) proteasomal function. Ub, ubiquitin.