Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ubiquitin (Ub) is a highly conserved small protein present universally in eukaryotic cells, which is covalently attached to substrate proteins by a cascade system, consisting of activating (E1), conjugating (E2), and/or ligating (E3) enzymes. The modification of cellular proteins with Ub targets them for degradation by a large multisubunit protease, called the 26S proteasome. The unexpected existence of many genes encoding E2 and E3 reveals that a number of distinct Ub-ligating pathways operate for selective proteolysis in cells, implying its involvement in divergent biologically important processes. Currently, it becomes clear that a set of novel molecules with a structural similarity to Ub, called Ub-like proteins (Ubls), is present in various eukaryotic cells. They are divided into two subclasses: type-1 Ubls with small sizes, such as SUMO1 and NEDD8, that are ligated to target proteins in a fashion similar, but not identical, to the ubiquitination pathway, and another type-2 Ubls that contain Ub-like structure in a variety of different classes of large proteins having apparently distinct functions, such as Rad23, Elongin B, and Parkin. Ub and type-1 Ubls are central players consisting of a new type of post-translational protein-modifying system, although the significance of type-2 Ubl remains obscure.
 ...
PMID:The ligation systems for ubiquitin and ubiquitin-like proteins. 985 35

The contribution of genetic factors to the pathogenesis of Parkinson's disease (PD) is supported by the demonstration of the high concordance in twins studies using positron emission tomography (PET), the increased risk among relatives of PD patients in case-control and family studies, and the existence of familial PD and parkinsonism by single gene defect. Recently several genes have been mapped and/or identified. Alpha-synuclein is involved in a rare dominant form of familial PD with dopa-responsive parkinsonism features and Lewy body-positive pathology. In contrast, parkin is responsible for the autosomal recessive form (AR-JP) of early onset PD with Lewy body-negative pathology. The clinical features of this form include early onset (in the 20s), levodopa-responsive parkinsonism, diurnal fluctuation, and slow progression of the disease. Parkin consists of 12 exons and the estimated size is over 1.5 Mb. To date, variable mutations such as deletions or point mutations resulting in missense and nonsense changes have been reported in AR-JP patients. In addition, the localization of parkin indicates that parkin may be involved in the axonal transport system. More recently we have found that parkin interacts with the ubiquitin-conjugating enzyme E2 and is functionally linked to the Ub-proteasome pathway as a ubiquitin ligase, E3. These findings fit the characteristics of a lack of Lewy bodies (these are cytoplasmic inclusions that are considered to be a pathological hallmark). Our findings should enhance the exploration of the mechanisms of neuronal death in PD as well as other neurodegenerative disorders of which variable inclusion bodies are observed.
 ...
PMID:Autosomal recessive juvenile parkinsonism: a key to understanding nigral degeneration in sporadic Parkinson's disease. 1103 96

In the recent years, many genes involved in inherited neurological disorders have been identified, and the achievement of the human genome project should accelerate their discovery. For common disorders which are of multifactorial origin, the identification of genetic susceptibility factors is still difficult. However, the study of rare monogenic forms of these disorders has proven to be fruitful. An example is Parkinson's disease, in which mutations in the alpha synculein gene are responsible for an autosomal dominant form. The study of alpha-synculein led to the conclusion that this protein is a major component of Lewy bodies, which constitute the pathological hallmark of the disease. The study of autosomal recessive forms allowed to demonstrate the relative frequency and the large variety of mutations in the Parkin gene. Parkin is probably involved in ubiquitination of proteins before their degradation by the proteasome and the identification of its cellular targets should allow the understanding of the specificity of neurodegenerative process in the human disease.
 ...
PMID:[The genome and neurology. The example of Parkinson's disease]. 1126 Dec 51

Parkin is a product of the Park2 gene the mutation of which causes autosomal recessive juvenile parkinsonism (AR-JP) characterized by selective dopaminergic neuronal death and absence of Lewy bodies. Recently we found that parkin is directly linked to the ubiquitin (Ub)-proteasome pathway as a Ub-protein ligase (E3) collaborating with a Ub-conjugating enzyme (E2) UbcH7. Here we analysed by in situ hybridization the expression of mRNAs for parkin and UbcR7 (rat orthologue of human UbcH7) in the developing rat brain. Parkin mRNA increased in parallel with neuronal maturation, but was unevenly distributed in various brain regions after four postnatal days. The expression pattern of the UbcR7 mRNA was almost identical to that of the parkin mRNA in all cases examined. Both parkin and UbcR7 mRNAs were distributed in neurones but not glial cells. Our findings indicate that parkin is expressed not only in the substantia nigra, but also uniformly in various brain regions in a development-dependent manner. Co-expression of UbcR7 with parkin suggests that UbcR7 may interact with parkin in vivo for ubiquitination of yet unidentified target protein(s).
 ...
PMID:Developmental changes in the expression of parkin and UbcR7, a parkin-interacting and ubiquitin-conjugating enzyme, in rat brain. 1141 39

Mutations in the gene encoding parkin cause an autosomal recessive juvenile-onset form of Parkinson's disease. Parkin functions as a RING-type E3 ubiquitin-ligase, coordinating the transfer of ubiquitin to substrate proteins and thereby targeting them for degradation by the proteasome. We now report that the extreme C terminus of parkin, which is selectively truncated by a Parkinson's disease-causing mutation, functions as a class II PDZ-binding motif that binds CASK, the mammalian homolog of Caenorhabditis elegans Lin-2, but not other PDZ proteins in brain extracts. Importantly, parkin co-localizes with CASK at synapses in cultured cortical neurons as well as in postsynaptic densities and lipid rafts in brain. Further, parkin associates not only with CASK but also with other postsynaptic proteins in the N-methyl d-aspartate (NMDA) receptor-signaling complex, in rat brain in vivo. Finally, despite exhibiting E2-dependent ubiquitin ligase activity, rat brain parkin does not ubiquitinate CASK, suggesting that CASK may function in targeting or scaffolding parkin within the postsynaptic complex rather than as a direct substrate for parkin-mediated ubiquitination. These data implicate for the first time a PDZ-mediated interaction between parkin and CASK in neurodegeneration and possibly in ubiquitination of proteins involved in synaptic transmission and plasticity.
 ...
PMID:Parkin and CASK/LIN-2 associate via a PDZ-mediated interaction and are co-localized in lipid rafts and postsynaptic densities in brain. 1167 92

Autosomal recessive juvenile parkinsonism (AR-JP) is one of the most common forms of familial Parkinson's disease. AR-JP is characterized by selective and massive loss of dopaminergic neurons in the substantia nigra of the midbrain and absence of Lewy bodies, the pathological hallmark of idiopathic Parkinson's disease. Parkin, the causative gene of AR-JP, encodes a 52-kDa protein that is a RING-type ubiquitin (Ub) protein ligase (E3) collaborating with a Ub-conjugating enzyme (E2) belonging to a cognate class of UbcH7 or UbcH8. Analysis of parkin mutations in AP-JP patients reveals that the functional loss of parkin as an E3 enzyme is the molecular basis of AR-JP. Thus it is now clear that AR-JP is due to failure of proteolysis mediated by the Ub-proteasome system and accumulation of as yet unidentified protein(s) causes nigral neuronal death without formation of Lewy bodies. These findings should shed new light on the mechanisms underlying neurodegeneration in sporadic Parkinson's disease as well as AR-JP.
 ...
PMID:Parkin is linked to the ubiquitin pathway. 1169 61

The identification of three genes and several additional loci associated with inherited forms of levodopa-responsive PD has confirmed that this is not a single disorder. Yet, analyses of the structure and function of these gene products point to the critical role of protein aggregation in dopaminergic neurons of the substantia nigra as the common mechanism leading to neurodegeneration in all known forms of this disease. The three specific genes identified to date--alpha-synuclein, Parkin, and ubiquitin C terminal hydrolase L1--are either closely involved in the proper functioning of the ubiquitin-proteasome pathway or are degraded by this protein-clearing machinery of cells. Knowledge gained from genetically transmitted PD also has clear implications for nonfamilial forms of the disease. Lewy bodies, even in sporadic PD, contain these three gene products, particularly abundant amounts of fibrillar alpha-synuclein. Increased aggregation of alpha-synuclein by oxidative stress, as well as oxidant-induced proteasomal dysfunction, link genetic and potential environmental factors in the onset and progression of the disease. The biochemical and molecular cascades elucidated from genetic studies in PD can provide novel targets for curative therapies.
 ...
PMID:Recent advances in the genetics and pathogenesis of Parkinson disease. 1237 Apr 84

Mutations in the parkin gene cause autosomal recessive inherited juvenile parkinsonism (ARJP) and account for the majority of cases of inherited Parkinson's disease (PD) of young onset (<45 years of age). Patients with parkin mutations commonly have atypical clinical features such as dystonia at onset, hyper-reflexia, diurnal fluctuations, and sleep benefit; however, parkin mutation patients with both typical PD symptoms and older age of onset have been identified. Parkin is a ubiquitin protein ligase (E3), a component in the pathway that attaches ubiquitin to specific proteins, designating them for degradation by the proteasome. Several substrates for parkin have been identified (CDCrel-1, o-glycosylated alpha-synuclein, parkin associated endothelin-like cell receptor, and synphilin). The role of these substrates in the pathogenesis of ARJP is under active study. Most patients with parkin mutations lack Lewy bodies, suggesting that functional parkin is involved in the formation of these highly ubiquitinated inclusions. Furthermore, the recognition that parkin mutations can lead to a disorder clinically similar to sporadic PD, but presumably lacking Lewy bodies, calls into question the necessity of Lewy bodies for the diagnosis of PD and nigral cell death. Studies of parkin are increasing the focus on the role of the ubiquitin-proteasome system in the pathogenesis of both familial and sporadic PD.
 ...
PMID:Significance of the parkin gene and protein in understanding Parkinson's disease. 1204 48

Parkinson's disease is a neurodegenerative disorder characterized by the progressive degeneration of the dopaminergic nigrostriatal pathway, and the presence of Lewy bodies. Over the past few years, several genes involved in inherited forms of the disease have been uncovered. In a small number of families with autosomal dominant inheritance, mutations have been identified in the genes encoding a-synuclein and ubiquitin carboxy-terminal hydrolase L1. Mutations in the parkin gene are a common cause of autosomal recessive parkinsonism with early onset, and also account for more than 15% of isolated cases with onset before age 45. The function of Parkin, a ubiquitin ligase involved in the degradation of protein substrates by the ubiquitin-proteasome pathway, highlights that ubiquitin-mediated proteolysis may play an important role in the pathophysiology of idiopathic Parkinson's disease.
 ...
PMID:[Parkin, alpha-synuclein and other molecular aspects of Parkinson's disease]. 1213 40

Parkinson's disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra and by the presence of ubiquitinated cytoplasmic inclusions known as Lewy bodies. Alpha-synuclein and Parkin are two of the proteins associated with inherited forms of PD and are found in Lewy bodies. Whereas numerous reports indicate the tendency of alpha-synuclein to aggregate both in vitro and in vivo, no information is available about similar physical properties for Parkin. Here we show that overexpression of Parkin in the presence of proteasome inhibitors leads to the formation of aggresome-like perinuclear inclusions. These eosinophilic inclusions share many characteristics with Lewy bodies, including a core and halo organization, immunoreactivity to ubiquitin, alpha-synuclein, synphilin-1, Parkin, molecular chaperones, and proteasome subunit as well as staining of some with thioflavin S. We propose that the process of Lewy body formation may be akin to that of aggresome-like structures. The tendency of wild-type Parkin to aggregate and form inclusions may have implications for the pathogenesis of sporadic PD.
 ...
PMID:Parkin accumulation in aggresomes due to proteasome impairment. 1236 39


1 2 3 4 5 6 7 8 9 10 Next >>