<unk> on’s disease PARK2 (OMIM *602544) is the<unk> gene that may cause a form of autosomal recessive juvenile<unk> on disease (OMIM 600116) due to a mutation in the<unk> protein. This form of genetic mutation may be one of the most common known genetic causes of early-onset<unk> on disease. In one study of patients with onset of<unk> on disease prior to age 40 (10% of all PD patients), 18% had<unk> mutations, with 5% homozygous mutations. Patients with an autosomal recessive family history of<unk> onism are much more likely to carry<unk> mutations if age at onset is less than 20 (80% vs. 28% with onset over age 40). Patients with<unk> mutations (PARK2) do not have Lewy bodies. Such patients develop a syndrome that closely resembles the sporadic form of PD; however, they tend to develop symptoms at a much younger age. In humans, loss-of-function mutations in<unk> PARK2 gene have been implicated in 50% of inherited and 15% of juvenile-onset sporadic forms of<unk> on’s disease (PD). While PD is traditionally regarded a late-onset neurodegenerative condition characterised by alpha-synuclein-enriched Lewy bodies, autosomal recessive PD due to<unk> mutations is often early onset and lack the ubiquitinated protein deposits pathognomonic for sporadic PD.<unk> mutant PD could also involve loss of noradrenergic neurons in the locus coeruleus alongside the hallmark degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). However, its symptoms resembles those of idiopathic PD, with patients presenting with resting tremors, postural instability and bradykinesia. While mitochondria are essential for ATP generation in any eukaryotic cell, catecholaminergic neurons are particularly reliant on their proper function for clearance of reactive oxygen species produced by dopamine metabolism, and to supply high energy requirements of catecholamine synthesis. Their susceptibility to oxidative damage and metabolic stress render catecholaminergic neurons vulnerable to neurotoxicity associated with aberrant regulation of mitochondrial activity, as is postulated to occur in both inherited and idiopathic PD. For example, enhanced oxidative stress in neurons, skeletal muscle and platelets, corresponding with reduced activity of complex I in the electron transport chain were reported in PD patients, while deletions in the mitochondrial genome were found in the SNpc. In accordance with its critical role in mitochondrial quality control, more than 120 pathogenic, PD-inducing mutations have been characterised on<unk>  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<unk> function. The discovery of numerous non-mitochondrial<unk> substrates reinforces the importance<unk> in neuronal homeostasis, beyond its role in mitochondrial regulation. Potent neuroprotective abilities of<unk> in attenuating dopaminergic neurotoxicity, mitochondrial swelling and excitotoxicity were demonstrated in cell cultures over-expressing<unk>  although the existence of such mechanisms at physiological<unk> levels in vivo is yet unconfirmed. Another<unk> substrate, synphilin-1 (encoded by SNCAIP), is an alpha-synuclein interacting protein that is enriched in the core of Lewy bodies and ubiquitinated by<unk> in a manner abolished by familial PD-associated mutations.<unk> 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.<unk> 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<unk> mutant PD. Similarly, native<unk> 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.<unk> 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,<unk> 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<unk> mutations are localised to RING1 and might impair its ability to bind and downregulate the p53 promoter, leading to enhanced p53 expression.<unk> mutant PD patients also exhibit a four-fold elevation in p53 immunoreactivity, insinuating that failure of<unk> mediated anti-apoptosis might be involved in etiology of PD. Tumourigenesis Consistent with<unk> s potent anti-tumourigenic abilities, negative mutations and deletions have been reported in various tumours. For example, PARK2 copy number was reduced in 85% of glioblastoma samples while lung cancers were associated with heterozygous deletion of PARK2 at 6q25-q27 locus.<unk> deficiency further diminished disease-free survival in infrared-irradiated mice without increasing tumour incidence rate, suggesting that<unk> deficiencies increase susceptibility to tumour-promoting events, rather than initiating tumour formation. Similarly, chromosomal breaks in PARK2 suppressed expression of afadin scaffold protein in breast cancer, thereby comprising epithelial integrity, enhancing metastatic potential and worsening overall prognosis. Haploinsufficient PARK2 expression, either due to reduced copy number or DNA hypermethylation, was further detected in spontaneous colorectal cancer where it accelerated all stages of intestinal adenoma development in mouse models.<unk> is therefore a potent modulator of tumour progression, without directly instigating tumourigenesis.
Parkin 
Peripherin
CEPP
Tetraspanin
Dystrophin
Alpha-synuclein
Huntingtin-interacting protein 1
MSin3 interaction domain