Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parkin, a RING-type ubiquitin ligase, is the product of the gene responsible for autosomal recessive juvenile parkinsonism. A reverse strand gene located upstream of the parkin gene in the human genome has been identified. The gene product, termed Glup/PACRG, forms a large molecular chaperone complex containing heat shock proteins 70 and 90 and chaperonin components. Glup suppressed cell death induced by accumulation of unfolded Pael receptor (Pael-R), a substrate of Parkin. On the other hand, Glup facilitated the formation of inclusions consisting of Pael-R, molecular chaperones, protein degradation molecules, and Glup itself, when proteasome is inhibited. Glup knockdown attenuated the formation of Pael-R inclusions, which resulted in the promotion of cell death with extensive vacuolization. Moreover, Glup turned out to be a component of Lewy bodies in Parkinson's disease cases. These data suggest that Glup may play an important role in the formation of Lewy bodies and protection of dopaminergic neurons against Parkinson's disease.
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PMID:A product of the human gene adjacent to parkin is a component of Lewy bodies and suppresses Pael receptor-induced cell death. 1453 70

Leprosy is caused by Mycobacterium leprae and affects about 700,000 individuals each year. It has long been thought that leprosy has a strong genetic component, and recently we mapped a leprosy susceptibility locus to chromosome 6 region q25-q26 (ref. 3). Here we investigate this region further by using a systematic association scan of the chromosomal interval most likely to harbour this leprosy susceptibility locus. 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. Possession of as few as two of the 17 risk alleles was highly predictive of leprosy. This was confirmed in a sample of 975 unrelated leprosy cases and controls from Brazil in whom the same alleles were strongly associated with leprosy. Variants in the regulatory region shared by PARK2 and PACRG therefore act as common risk factors for leprosy.
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PMID:Susceptibility to leprosy is associated with PARK2 and PACRG. 1473 77

In early 2003, an international team of scientists conducted a genome scan in Vietnamese multiplex leprosy families and found that susceptibility to leprosy was significantly linked to region q25 on the long arm of chromosome 6. Further confirmation of the chromosome 6 locus was provided by high-resolution linkage mapping in simplex leprosy families. Now, in a continuation of these findings, the team has pinpointed the chromosome 6 susceptibility locus to the 5' regulatory promoter region shared by both the Parkinson's disease gene PARK2 and its co-regulated gene PACRG. The surprising discovery has important implications for the understanding of leprosy pathogenesis and for the strategy of genetic analysis of infectious diseases.
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PMID:Linkage of leprosy susceptibility to Parkinson's disease genes. 1530 85

The elucidation of the genetic control of susceptibility to common infectious diseases is expected to provide new and more effective tools for prevention and control of some of the most pressings health needs on a global scale. A major advantage of whole genome based genetic approaches is that no a priori assumptions about mechanisms of pathogenesis need to be made in these studies. Hence, genetic studies can identify previously unrecognized pathways of disease susceptibility and tag critical pathogenic events for further biochemical, immunological or physiological analysis. We have applied this strategy to leprosy, a disease that still claims 400,000 new cases each year. We identified genetic variants in the shared promoter region of the PARK2 and PACRG genes as major risk factors of leprosy susceptibility. Both encoded proteins are part of the cellular ubiquitination system. Specifically, PARK2, the cause of early onset Parkinson's disease, is an E3 ligase that likely is involved in controlled proteolysis, the cellular anti-oxidants response and the regulation of innate immune responsiveness. In addition, numerous E3 ligases have recently been shown to be critical regulators of immunity. While the specific role of PARK2/PACRG in leprosy pathogenesis remains unknown, a number of experimentally testable scenarios can be developed to further explore the role of these proteins in anti-Mycobacterium leprae host responsiveness.
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PMID:Genetic predisposition to leprosy: A major gene reveals novel pathways of immunity to Mycobacterium leprae. 1697 74

Parkin is the gene responsible for a familial form of Parkinson's disease (PD) termed autosomal recessive juvenile parkinsonism (AR-JP)/PARK2. Parkin has been shown to protect cells from endoplasmic reticulum (ER) stress and oxidative stress, presumably due to its ubiquitin ligase (E3) activity that targets proteins for proteasomal degradation. Although the authors showed that parkin is upregulated in response to ER stress, subsequent reports suggest that it does not represent a universal unfolded protein response (UPR). Here the authors report different regulation of parkin in response to ER stress in different cell lines, demonstrating upregulation of parkin as a cell type-specific response to ER stress. 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. In parallel with these studies, similar upregulation of the parkin coregulated gene (PACRG)/gene adjacent to parkin (Glup) was also observed by ER stress. Luciferase assays failed to detect the transcriptional activation of 500 bp parkin/Glup promoter in response to ER stress. These results indicate that induction of parkin by ER stress represents a cell type-specific response.
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PMID:Cell type-specific upregulation of Parkin in response to ER stress. 1746 79

A homologue of mammalian PACRG was identified in Sarkosyl-extracted Chlamydomonas axonemes as a protein that may interact with Rib72 (a component of the protofilament ribbon within the outer doublet microtubules). PACRG is a protein whose expression is co-regulated with the Parkin gene implicated in Parkinson's disease. Although subsequent analyses did not confirm a Rib72-PACRG interaction, both proteins display similar localization in the axoneme. Immuno-localization of PACRG required pretreatment of the axoneme with Sarkosyl, suggesting that the antigen is buried in the wall of the microtubule. Indirect immunofluorescence localized PACRG to the entire length of the axoneme and the basal body, and immuno-electron microscopy showed that the PACRG antigen is densely distributed along the outer doublets in frayed axonemes. In thin-section images, the PACRG signals were frequently found between the A- and B-tubules of adjacent outer doublets. From these and other results, we propose that PACRG is a structural component of the doublet and triplet microtubules possibly involved in inter-tubule linkage.
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PMID:Axonemal localization of Chlamydomonas PACRG, a homologue of the human Parkin-coregulated gene product. 1765 7

Mutations in the gene encoding the E3 ubiquitin-protein ligase parkin have been shown to be a common genetic cause of familial early-onset Parkinson's disease (PD). In addition to its function in the ubiquitin-proteasome system (UPS), parkin has been ascribed general neuroprotective properties. Stress and mutation induced decreases in parkin solubility leading to compromised cytoprotection have recently been reported. We systematically investigated whether PD-related stresses including MG132 and epoxomicin (proteasomal impairment), tunicamycin (unfolded protein stress), and rotenone (mitochondrial dysfunction) resulted in expressional changes of parkin and other E3 ubiquitin ligases (dorfin, SIAH-1). Rotenone and tunicamycin did not change parkin mRNA levels, whereas proteasomal inhibition resulted in a reduction of parkin mRNA in PC12 cells as well as in SH-SY5Y cells. Therefore, surprisingly, cells did not react with a compensatory parkin upregulation under proteasomal inhibition, although, in parallel, parkin protein shifted to the insoluble fraction, reducing soluble parkin levels in the cytosol. Since the mRNA of the parkin-coregulated gene PACRG paralleled the parkin mRNA at least partly, we suspect a promoter-driven mechanism. Our study, therefore, shows a link between proteasomal impairment and parkin expression levels in cell culture, which is intriguing in the context of the described and debated proteasomal dysfunction in the substantia nigra of PD patients.
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PMID:Proteasomal inhibition reduces parkin mRNA in PC12 and SH-SY5Y cells. 1858 49

PArkin Co-Regulated Gene is a gene that shares a bidirectional promoter with the Parkinson's disease associated gene parkin. The encoded protein (PACRG) is found in Lewy bodies and glial cytoplasmic inclusions, the pathological hallmarks of parkinsonian disorders. To investigate the function and regulation of PACRG, cells were treated with the proteasomal inhibitor, MG-132. As previously reported with parkin, inhibition of the proteasome resulted in the formation of aggresomes that contained endogenous PACRG. Increased levels of exogenous PACRG resulted in an increase in aggresome formation, and conferred significant resistance to aggresome disruption and cell death mediated by microtubule depolymerisation. In contrast, shRNA mediated knockdown of PACRG significantly reduced aggresome numbers. Elevated levels of PACRG also resulted in increased autophagy, as demonstrated by biochemical and quantitative analysis of autophagic vesicles, whereas lowered levels of PACRG resulted in reduced autophagy. These results suggest a role for PACRG in aggresome formation and establish a further link between the UPS and autophagy.
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PMID:Parkin co-regulated gene is involved in aggresome formation and autophagy in response to proteasomal impairment. 2265 56