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2.2. Parkin
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2.2.1. Parkin and ubiquitylation pathways
In 1998, mutations in the parkin gene were identified as a cause of autosomal
recessive PD with juvenile onset in Japanese families [157]. Since then, more than
hundred different mutations have been described in patients of diverse ethnic
backgrounds, accounting for the majority of autosomal recessive parkinsonism [158,
159]. The parkin gene encodes a cytosolic 465 amino acid protein with a ubiquitin-
like domain (UBL) at the N-terminus and a RBR domain close to the C-terminus,
consisting of two RING finger motifs which flank a cysteine-rich in-between RING
finger domain. The presence of the RBR domain suggested that parkin has an E3
ubiquitin ligase activity, mediating the covalent attachment of ubiquitin to substrate
proteins. A well known function of ubiquitin is to target substrates for degradation by
the proteasome, which requires a chain of at least four ubiquitin moieties in length.
Genetic and biochemical studies revealed that pathogenic mutations induce a loss of
parkin function, leading to the hypothesis that the accumulation of parkin substrates
causes neurotoxicity and results in the death of dopaminergic neurons. From yeast-
two-hybrid and pull-down approaches a long list of putative parkin substrates has
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emerged (rev. in [160]). Curiously, these substrates do not fit into a common pathway
and so far did not contribute mechanistic insight into the functional role of parkin.
Moreover, data on the accumulation of putative parkin substrates in parkin knockout
mice or brains from patients carrying parkin mutations are conflicting. There is
increasing experimental evidence that parkin can induce proteasome-independent
ubiquitylation [161-166]. Depending on the number of ubiquitin moieties attached
and the mode of ubiquitin linkage, ubiquitylation serves a remarkably wide range of
physiological functions (rev. in [167-170]). Ubiquitin harbors seven lysine residues,
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