Disease relevance of PARK2

• Inherited mutations in PARK2, the gene encoding parkin, cause selective degeneration of catecholaminergic neurons in the substantia nigra and locus coeruleus of the brainstem, resulting in early-onset parkinsonism [1].
• Abnormal methylation of the common promoter of PARK2 and PACRG was observed in 26% of patients with acute lymphoblastic leukemia and 20% of patients with chronic myelogenous leukemia (CML) in lymphoid blast crisis, but not in ovarian, breast, lung, neuroblastoma, astrocytoma or colon cancer cells [2].
• Abnormal methylation of the common PARK2 and PACRG promoter is associated with downregulation of gene expression in acute lymphoblastic leukemia and chronic myeloid leukemia [2].
• PARK2/PACRG polymorphisms and susceptibility to typhoid and paratyphoid fever [3].
• In 197 Vietnamese families we found a significant association between leprosy and 17 markers located in a block of approx. 80 kilobases overlapping the 5' regulatory region shared by the Parkinson's disease gene PARK2 and the co-regulated gene PACRG [4].
• Phosphorylation by Cdk5 may contribute to the accumulation of toxic Parkin substrates and decrease the ability of dopaminergic cells to cope with toxic insults in Parkinson disease [5].
• These studies provide a new perspective on the potential nature of pathogenic alpha-synuclein and parkin interactions in Parkinson disease [6].

Psychiatry related information on PARK2

• Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies [7].
• Rapid eye movement sleep behavior disorder in parkinsonism with parkin mutations [8].
• [(123)I]meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is a useful diagnostic tool to differentiate Parkinson's disease and dementia with Lewy bodies (Lewy body disease) from other related movement disorders, PARK2, and Alzheimer's disease [9].
• Co-occurrence of restless legs syndrome and Parkin mutations in two families [10].
• CONCLUSIONS: Our patients with parkin mutation performed poorly on neuropsychological tests compared to those with YOPD [11].

High impact information on PARK2

• Progress has been made in understanding some of the mechanisms of toxicity: Parkin is an E3 ubiquitin ligase and DJ-1 and PINK1 appear to protect against mitochondrial damage [12].
• In contrast, mutations in several recessive genes (parkin, DJ-1, and PINK1) produce neuronal cell loss but generally without protein aggregation pathology [12].
• Here, we have identified Parc, a Parkin-like ubiquitin ligase, as a cytoplasmic anchor protein in p53-associated protein complexes [13].
• Parkin specifically ubiquitinates this receptor in the presence of ubiquitin-conjugating enzymes resident in the endoplasmic reticulum and promotes the degradation of insoluble Pael receptor, resulting in suppression of the cell death induced by Pael receptor overexpression [14].
• An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin [14].

Chemical compound and disease context of PARK2

• Three recent reports demonstrate that parkin can protect neurons from diverse cellular insults, including alpha-synuclein toxicity, proteasomal dysfunction, Pael-R accumulation, and kainate-induced excitotoxicity [15].
• Here we show that parkin significantly increased dopamine uptake in the human dopaminergic neuroblastoma cell line SH-SY5Y [16].
• Moreover, normal cardiac uptake of MIBG might be of potential diagnostic value to indicate the absence of Lewy body pathology, even in patients with levodopa-responsive Parkinsonism, as in PARK2 [17].
• Here, we show that overexpression of parkin protected human DA neuroblastoma cell line (SH-SY5Y) against apoptosis induced by DA or 6-OHDA, but not by H(2)O(2) or rotenone [18].
• To address this issue, we established an E3 assay system using maltose-binding protein-fused Parkin purified from Escherichia coli [19].

Biological context of PARK2

• With respect to genome-wide screens, a major breakthrough has been reported this year; variants in the regulatory region shared by PARK2 and PACRG have been identified as being common risk factors for leprosy [20].
• Loss of heterozygosity analysis of primary ovarian tumors by use of polymorphic markers in the 6q26 region demonstrated 72% LOH in the center of the PARK2 gene, the highest of any of the markers tested [21].
• A gene for autosomal recessive juvenile parkinsonism (ARJP; HGMW-approved symbol PARK2; MIM 600116) has recently been mapped to a 17-cM interval on chromosome 6q25.2-q27 [22].
• Although within the PARK2/PACRG gene cluster the PARK2_e01(-2599) allele T was most strongly associated with leprosy (OR approximately 3-5), the association with typhoid is much less strong [3].
• Autosomal recessive mutations in the parkin gene (PARK2) have been identified as a common cause of familial and also sporadic, early-onset parkinsonism (EOPD): point mutations, exonic deletions, and duplications or triplications have been described [23].

Anatomical context of PARK2

• We have studied the role of promoter hypermethylation in the regulation of PARK2 and PACRG expression in different tumor cell lines and primary patient samples [2].
• The absence of Lewy bodies in patients with parkin mutations suggests that parkin might be required for the formation of Lewy bodies [24].
• Parkin fails to specifically ubiquitinate and enhance the degradation of L166P and M26I mutant DJ-1, but instead promotes their stability in cultured cells [25].
• These findings demonstrate that Parkin is an E3 enzyme and suggest that it is involved in the ubiquitination pathway for misfolded proteins derived from endoplasmic reticulum and contributes to protection from neurotoxicity induced by unfolded protein stresses [26].
• Double labeling with confocal microscopy of DLB midbrain sections revealed that approximately 90% of anti-alpha S-reactive LBs were also detected by a parkin antibody to amino acids 342 to 353 [7].

Associations of PARK2 with chemical compounds

• These patients were evaluated previously for the presence of parkin mutations (PARK2) and were found to be negative [27].
• Because both Parkin and alpha-synuclein can regulate the activity of the dopamine transporter, we investigated whether they influenced ubiquitin lysine 63-linked chain assembly [28].
• We determined that Parkin functions with UbcH13/Uev1a, a dimeric ubiquitin-conjugating enzyme, to assemble ubiquitin lysine 63-linked chains [28].
• Heterozygous carriers of a single Park2 mutation either were asymptomatic or developed clinical symptoms in late adulthood or after brief exposure to haloperidol therapy [29].
• Additionally, we show sensitivity of both endogenous synphilin-1 and parkin to proteolytic dysfunction and their co-localization in aggresomes formed in response to the proteasome inhibitor MG-132 [30].
• 2-Mercaptoethanol (2-ME) and tunicamycin increased the expression of parkin in SH-SY5Y (H) cells, Neuro2a cells, Goto-P3 cells, but not in SH-SY5Y (J) cells and IMR32 cells [31].
• Compound heterozygous parkin mutations (EX 3_6 del and EX 5 del) caused EOPD in this family, but the A265G variant in the HS1BP3 gene, previously considered to be responsible for ET, was probably not pathogenically related to the ET in this family [32].

Physical interactions of PARK2

• Here we show that parkin interacts with and ubiquitinates the alpha-synuclein-interacting protein, synphilin-1 [24].
• These results suggest that parkin interacts with alpha-synuclein and could contribute to the pathophysiology of PD more generally than was previously considered [33].
• Chemical cross-linking shows that pathogenic DJ-1 mutants exhibit impairments in homo-dimer formation, suggesting that parkin may bind to monomeric DJ-1 [25].
• Using the yeast two-hybrid system and co-immunoprecipitation methods, we identified synaptotagmin XI as a protein that interacts with parkin [34].
• Here we reported that Parkin selectively binds to RanBP2, which is localized in the cytoplasmic filament of the nuclear pore complex and belongs to the small ubiquitin-related modifier E3 ligase family [35].

Enzymatic interactions of PARK2

• Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease [24].
• Parkin specifically ubiquitinates the unfolded Pael-R and promotes its degradation, resulting in suppression of cell death induced by the accumulation of unfolded Pael-R [36].
• We hypothesized that these two gene products interact functionally, namely, that parkin ubiquitinates alpha-synuclein normally and that this process is altered in autosomal recessive PD [37].

Regulatory relationships of PARK2

• Our results and the results of others indicate that Parkin can promote both lysine 48- and lysine 63-linked ubiquitin chains. alpha-Synuclein also stimulated the assembly of lysine 63-linked ubiquitin chains [28].
• A product of the human gene adjacent to parkin is a component of Lewy bodies and suppresses Pael receptor-induced cell death [38].
• Furthermore, Parkin ubiquitinates and promotes the degradation of CDCrel-1 [39].
• INTERVENTIONS: Analysis of clinical characteristics and mutation analysis of the parkin and PTEN-induced kinase (PINK1) genes by direct sequencing and gene-dosage analysis using the multiplex ligation-dependent probe amplification technique [40].
• Parkin ubiquitinates and promotes the degradation of RanBP2 [35].

Other interactions of PARK2

• These results provide a molecular basis for the ubiquitination of Lewy-body-associated proteins and link parkin and alpha-synuclein in a common pathogenic mechanism through their interaction with synphilin-1 [24].
• We further show that familial-linked mutations in parkin disrupt the ubiquitination of synphilin-1 and the formation of the ubiquitin-positive inclusions [24].
• A small proportion of the cells overexpressing LRRK2 contain protein aggregates, and this proportion is greatly increased by coexpression of parkin [41].
• RT-PCR analysis of the eight genes localizing to FRA6E indicated that 50% of the genes, including PARK2, were down-regulated in one or more of the primary ovarian tumors analyzed [21].
• Moreover, insoluble Pael-R accumulates in the brains of AR-JP patients [36].

Analytical, diagnostic and therapeutic context of PARK2

• Fluorescence resonance energy transfer and immunoelectron microscopy showed that alphaS and parkin co-localized within brainstem and cortical LBs [7].
• In this study, we have investigated the distribution patterns of synphilin-1 and parkin proteins in control and sporadic PD brain tissue by immunohistochemistry (IH), immunoblotting, and immunoelectron microscopy (IEM) [30].
• We studied the PARK2-encoded protein Parkin by using immunohistochemistry on the same TMA [42].
• We studied a series of breast carcinomas for break of a CFS at 6q26, FRA6E, and its associated gene PARK2, using fluorescence in situ hybridization on tissue microarrays (TMA) [42].
• Taken together, our results indicate that the parkin gene therapy is effective against alpha-synucleinopathy, suggesting its potential suitability for patients with PD [43].

References