accordance with its critical role in mitochondrial quality control, more than 120 pathogenic, PD-inducing mutations have been characterised on parkin. Such mutations may be hereditary or stochastic and are associated with structural instability, reduced catalytic efficiency and aberrant substrate binding and ubiquitination. Mutations can generally be categorised into three groups, depending on their location. Firstly, those clustered around Zn-coordinating residues on RING and IBR might compromise structural integrity and impair catalysis. A second class of mutations, including Thr240Arg, affect residues in and around the E2 binding site and alter autoinhibition of RING1 by REP. Finally, Cys431Phe and Gly430Asp mutations impair ligase activity at the catalytic site and significantly reduce parkin function. The discovery of numerous non-mitochondrial parkin substrates reinforces the importance parkin in neuronal homeostasis, beyond its role in mitochondrial regulation. Potent neuroprotective abilities of parkin in attenuating dopaminergic neurotoxicity, mitochondrial swelling and excitotoxicity were demonstrated in cell cultures over-expressing parkin, although the existence of such mechanisms at physiological parkin levels in vivo is yet unconfirmed. Another parkin substrate, synphilin-1 (encoded by SNCAIP), is an alpha-synuclein interacting protein that is enriched in the core of Lewy bodies and ubiquitinated by parkin in a manner abolished by familial PD-associated mutations. Parkin might promote aggregation of alpha-synuclein and synphilin-1 into Lewy bodies, which are conjugated to Lys63-linked poly-Ub chains and directed towards autophagic degradation. Parkin mutations therefore inhibit this mechanism, leading to toxic accumulation of soluble proteins that overloads the proteasome. Protein aggregation triggers neuronal toxicity, whilst accounting for lack of ubiquitinated Lewy bodies in parkin-mutant PD. Similarly, native parkin reduces death of SH-SY5Y neurons by ubiquitinating other Lewy body constituents, such as the p38 subunit of aminoacyl-tRNA synthetase complex and far upstream element-binding protein 1 through addition of Lys48-linked poly-Ub chains and directing them towards proteasomal degradation. Parkin also influences axonal transport and vesicle fusion through ubiquitination of tubulin and synaptotagmin XI (SYT11) respectively, giving it a modulatory role in synapse function. Finally, parkin protects dopaminergic neurons from cytotoxicity induced by PD-mimetic 6-OHDA, mediated by suppression of neuronal p53 expression and its downstream activation of the apoptotic cascade. Several PD-associated parkin mutations are localised to RING1 and might impair its ability to bind and downregulate the p53 promoter, leading to enhanced p53 expression. Parkin-mutant PD patients also exhibit a four-fold elevation in p53 immunoreactivity, insinuating that failure of parkin-mediated anti-apoptosis might be involved in etiology of PD. Tumourigenesis Consistent with parkin’s