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

Mutations in parkin are associated with various inherited forms of Parkinson's disease (PD). Parkin is a ubiquitin ligase enzyme that catalyzes the covalent attachment of ubiquitin moieties onto substrate proteins destined for proteasomal degradation. The substrates of parkin-mediated ubiquitination have yet to be completely identified. Using a yeast two-hybrid screen, we isolated the septin, human SEPT5_v2 (also known as cell division control-related protein 2), as a putative parkin-binding protein. SEPT5_v2 is highly homologous to another septin, SEPT5, which was recently identified as a target for parkin-mediated ubiquitination. SEPT5_v2 binds to parkin at the amino terminus and in the ring finger domains. Several lines of evidence have validated the putative link between parkin and SEPT5_v2. Parkin co-precipitates with SEPT5_v2 from human substantia nigra lysates. Parkin ubiquitinates SEPT5_v2 in vitro, and both SEPT5_v1 and SEPT5_v2 accumulate in brains of patients with ARJP, suggesting that parkin is essential for the normal metabolism of these proteins. These findings suggest that an important relationship exists between parkin and septins.
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PMID:SEPT5_v2 is a parkin-binding protein. 1455 52

Septin 3 is a novel member of the septin subfamily of GTPase domain proteins that was recently identified in human neuronal cells. These proteins are involved in vesicle trafficking, neurite outgrowth, and neurofibrillary tangle formation; however, the expression and functional role of septin 3 in normal neuronal tissues and as an etiological agent in neurological disorders is currently unclear. To further characterize these parameters, the present study analyzed the expression of three isoforms of septin 3 (A, B, and C) in fetal and adult human brains and polymorphism of the septin 3 exon 11 microsatellite in control, pure Alzheimer's disease (AD), Lewy body variant (LBV) of AD, and Parkinson's disease. Septin 3 mRNAs for isoforms A and B, but not C, were detected in the frontal cortex of fetus and adult human samples, as measured by reverse transcription-coupled polymerase chain reaction. Genotype analyses indicated that polymorphic septin 3 alleles were distributed in two peaks of frequency in both control and disease groups. Categorization of the alleles into short (S) and long (L) types revealed a significant difference between AD patients and controls (p = 0.034 by chi-square test). Furthermore, the S-allele homozygosity was significantly underrepresented in AD compared with control (p = 0.015 by chi-square test). These results suggest that polymorphism in exon 11 of septin 3 may have a determinative role in the pathogenesis of AD.
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PMID:Septin 3 gene polymorphism in Alzheimer's disease. 1520 Feb 38

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. It is urgently needed to elucidate the cause of the disease and to establish neuroprotective treatment. We have been working on the etiology and pathogenesis of PD for many years and we found selective loss of mitochondrial complex I and the alpha-ketoglutarate dehydrogenase complex in the nigral neurons of patients with PD. Our observation firmly established mitochondrial defects in PD. Mitochondrial respiratory failure induces oxidative damage in neurons, and we found increase in hydroxynonenal and 8-oxo-deoxyguanine, indices of oxidative damage, in the nigral neurons of PD. These abnormalities can trigger apoptotic cell death. The primary events which induce mitochondrial failure and oxidative damage are not known, however, it has been postulated that the interaction of genetic risk factors and environmental factors would initiate the degenerative process. Based on this assumption, we conducted genetic association studies by the candidate gene methods. We found that polymorphic mutations of superoxide dismutase-2 and 24-kDa subunit of mitochondrial complex I were associated increased risk of developing Parkinson's disease. While we were doing this genetic association study, we found a family, in which parkinsonian phenotype completely segregated with a polymorphic mutation of the superoxide dismutase-2 gene. In this family, 4 out of 6 siblings were affected with early onset parkinsonism and the parents were apparently normal. Thus the mode of inheritance appeared to be autosomal recessive and this type is now called as AR-JP or Park2. We confirmed the linkage of this type of familial Parkinson's disease to the superoxide dismutase loci that is located in the telomeric region of chromosome 6 by the linkage analysis using microsatellite markers in this region. Then we found another family, in which an affected patient showed lack of one of the microsatellite markers (D6S315), which we were using in the linkage analysis. This observation prompted us to initiate the molecular cloning of the disease gene utilizing D6S315 as the initial probe. The molecular cloning was done with the collaboration with Professor Nobuyoshi Shimizu of Keio University. We identified a novel gene and confirmed that mutations of this novel gene were found only in the patients with autosomal recessive Parkinson's disease. The novel gene was named parkin. We conducted mutational analysis on more than 700 families with Parkinson's disease. We also established a method to detect compound heterozygotes of parkin mutations. Mutinous of the parkin gene were found in approximately 50% of autosomal recessive families. Many kinds of exonic deletions and point mutations were found. This type of familial Parkinson's disease had been considered to be unique among Japanese, but since we started mutational analysis of the parkin gene, we confirmed the world wide distribution of parkin gene mutations. Then we analyzed functions of parkin protein with the collaboration with Dr. Keiji Tanaka of Tokyo Metropolitan Institute of Medical Sciences. We found that parkin protein was a ubiquitin-protein ligase of the ubiquitin system. Now we are working on the candidate substrates of parkin protein as a ubiquitin ligase. We found that CDCrel-1, a synaptic vesicle protein, was a candidate substrate of parkin protein. In addition, we found two additional candidate proteins, i.e., alpha-synuclein 22 and PAEL receptor, with the collaboration of Professor Denis Selkoe of Harvard Medical School and Dr. Ryosuke Takahashi of RIKEN, respectively. Accumulation of PAEL receptor in the endoplasmic reticulum causes endoplasmic reticulum stress and apoptotic cell death. We found evidence to indicate accumulation of PAEL receptor and the presence of endoplasmic reticulum stress in a patient with AR-JP (Park2). Thus our studies firmly established that a genetic defect of an enzyme in the ubiquitin-proteasome system induces selective nigral neuronal death. We indicated the important role of the ubiquitin-proteasome system in neurodegeneration in general. In many other neurodegenerative disorders, such as Alzheimer's disease, Huntington's disease, Machado-Joseph disease, dentatorubral-pallidoluysian atrophy, and ALS, ubiquitinated proteins are accumulated in neurons. Thus protein handling in the ubiquitin-proteasome system appears to be affected in these neurodegenerative disorders despite the difference in the primary defects. Our studies also suggest many potential approaches for the discovery of neuroprotective treatment for not only Parkinson's disease but also other neurodegenerative disorders.
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PMID:[Etiology and pathogenesis of Parkinson's disease: from mitochondrial dysfunctions to familial Parkinson's disease]. 1528 6

Parkin is a ubiquitin-protein isopeptide ligase. It has been suggested that loss of function in parkin causes accumulation and aggregation of its substrates, leading to death of dopaminergic neurons in Parkinson disease. Using the yeast two-hybrid screen, we isolated a RING finger protein that interacted with the N terminus of parkin in a Drosophila cDNA library. Interaction between human parkin and the mammalian RING finger protein homologue Nrdp1/FLRF, a ubiquitin-protein isopeptide ligase that ubiquitinates ErbB3 and ErbB4, was validated by in vitro binding assay, co-immunoprecipitation, and immunofluorescence co-localization. Significantly, pulse-chase experiments showed that cotransfection of Nrdp1 and parkin reduced the half-life of parkin from 5 to 2.5 h. Consistent with these findings, we further observed that degradation of CDCrel-1, a parkin substrate, was facilitated by overexpression of parkin protein. However, co-transfection of Nrdp1 with parkin reversed the effects of parkin on CDCrel-1 degradation. We conclude that Nrdp1 is a parkin modifier that accelerates degradation of parkin, resulting in a reduction of parkin activity.
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PMID:RING finger ubiquitin-protein isopeptide ligase Nrdp1/FLRF regulates parkin stability and activity. 1563 91

In Parkinson disease (PD), alpha-synuclein aggregates called Lewy bodies often involve and sequester Septin4 (Sept4), a polymerizing scaffold protein. However, the pathophysiological significance of this phenomenon is unclear. Here, we show the physiological association of Sept4 with alpha-synuclein, the dopamine transporter, and other presynaptic proteins in dopaminergic neurons; mice lacking Sept4 exhibit diminished dopaminergic neurotransmission due to scarcity of these presynaptic proteins. These data demonstrate an important role for septin scaffolds in the brain. In transgenic mice that express human alpha-synuclein(A53T) (a mutant protein responsible for familial PD), loss of Sept4 significantly enhances neuropathology and locomotor deterioration. In this PD model, insoluble deposits of Ser129-phosphorylated alpha-synuclein(A53T) are negatively correlated with the dosage of Sept4. In vitro, direct association with Sept4 protects alpha-synuclein against self-aggregation and Ser129 phosphorylation. Taken together, these data show that Sept4 may be involved in PD as a dual susceptibility factor, as its insufficiency can diminish dopaminergic neurotransmission and enhance alpha-synuclein neurotoxicity.
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PMID:Sept4, a component of presynaptic scaffold and Lewy bodies, is required for the suppression of alpha-synuclein neurotoxicity. 1729 45

Autosomal recessive juvenile parkinsonism (AR-JP), a common familial form of Parkinson's disease, is caused by mutations of human Parkin. To deepen the understanding of Parkin biology in an in vivo model of Drosophila, we attempted to characterize the function of Drosophila melanogaster Parkin and found that D. melanogaster Parkin exhibited UbcH8-dependent E3 ubiquitin-protein ligase activity. Using E2 binding and in vitro ubiquitination assays, UbcH8 preferentially was found to bind to Parkin mutants harboring functional RING1 domains, but failed to bind to mutants harboring point mutants with complete loss of function. This inability of UbcH8 binding to such mutants was accompanied by abrogation of an E3 ligase activity, indicating that D. melanogaster Parkin as an E3 ligase interacts with UbcH8 through its RING1 domain. An in vivo ubiquitination assay revealed that D. melanogaster Parkin existed in ubiquitinated form in vivo. Moreover, peanut and septin1, D. melanogaster septin proteins, were also ubiquitinated by D. melanogaster Parkin. Co-immunoprecipitation with membrane protein Syntaxin indicated direct binding of septin proteins to syntaxin, implicating their relevance in the exocytosis of dopamine in cells. Western blot analysis and DNA fragmentation indicated that the rate and efficiency of p53-dependent apoptosis were significantly higher in the presence of dopamine than without the septin proteins. Therefore, our findings in the present study demonstrate that Parkin possibly influences septin protein effects on p53-mediated apoptosis, helping to extend the utility of Drosophila as a model system for the study of neurodegeneration.
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PMID:Drosophila melanogaster Parkin ubiquitinates peanut and septin1 as an E3 ubiquitin-protein ligase. 1745 38

SEPT4 is a member of the mammalian septin family of GTPases. Mammalian septins are conserved proteins which form heteropolymers in vivo and which are implicated in a variety of cellular functions such as cytokinesis, exocytosis, and vesicle trafficking. However, their structural properties and modes of action are largely unknown. There is a limited, but as yet inconclusive, amount of experimental data suggesting that SEPT4 may accumulate in tau-based filamentous deposits and cytoplasmic inclusions in Alzheimer's and Parkinson's disease, respectively. Here we report an intermediate structure of the GTPase domain of human SEPT4 (SEPT4-G) during unfolding transitions induced by temperature. This partially unfolded intermediate, which is rich in beta-sheet and free of bound nucleotide, was plagued by irreversible aggregation. The aggregates have the ability to bind specific dyes such as Congo red and thioflavin-T, suggesting they are amyloid in nature. Under electron microscopy, fibers of variable diameter extending for several micrometers in length can be visualized. This is the first report of amyloid formation by a septin or domain thereof, and the capacity of SEPT4-G to form such fibrillar aggregates may shed some light on the current discussion concerning the formation of homo- and heteropolymers of septins in vitro.
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PMID:An intermediate structure in the thermal unfolding of the GTPase domain of human septin 4 (SEPT4/Bradeion-beta) forms amyloid-like filaments in vitro. 1776 58

Defects in cellular quality control mechanisms are thought to contribute to the neuropathology of Parkinson's disease (PD). Overexpressing heat shock proteins (HSPs) may constitute a powerful therapeutic strategy for PD, because they boost the ability of the cell to eliminate unwanted proteins. We investigated the neuroprotective potential of HSP70, HSP40, and H-BH, a constitutively active form of heat shock factor 1, in a rat model of PD based on adeno-associated virus (AAV) vector-mediated overexpression of CDCrel-1, a parkin substrate known to be toxic to dopaminergic neurons. AAV vector-mediated overexpression of H-BH and of HSP70 afforded similar levels of protection against CDCrel-1 toxicity, with approximately 20% improvement in survival of dopaminergic neurons as compared to the controls. The assessment of protection conferred was made using tyrosine hydroxylase (TH) and HuC/D immunohistochemistry and Fluoro-Gold retrograde tracing, and by observing the extent of preservation of spontaneous function and also the extent of drug-induced motor function. In contrast to H-BH and HSP70, HSP40 overexpression exacerbated CDCrel-1-mediated cell death. Real-time reverse transcriptase (RT)-PCR analysis showed that H-BH had the effect of upregulating endogenous HSP70 and HSP40 mRNA levels 10-fold and 4-fold over basal levels, respectively, whereas AAV vector-mediated HSP70 and HSP40 mRNA levels were over 100-fold higher. Our results suggest that a comparatively modest upregulation of multiple HSPs may be an effective approach for achieving significant neuroprotection in PD.
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PMID:HSP70 and constitutively active HSF1 mediate protection against CDCrel-1-mediated toxicity. 1839 26

The dual-specific kinase DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A) is the mammalian orthologue of the Drosophila minibrain (MNB) protein kinase and executes diverse roles in neuronal development and adult brain physiology. DYRK1A is overexpressed in Down syndrome (DS) and has recently been implicated in several neurodegenerative diseases. In an attempt to elucidate the molecular basis of its involvement in cognitive and neurodegeneration processes, we searched for novel proteins interacting with the kinase domain of DYRK1A in the adult mouse brain and identified septin 4 (SEPT4, also known as Pnutl2/CDCrel-2). SEPT4 is a member of the group III septin family of guanosine triphosphate hydrolases (GTPases), which has previously been found in neurofibrillary tangles of Alzheimer disease brains and in alpha-synuclein-positive cytoplasmic inclusions in Parkinson disease brains. In transfected mammalian cells, DYRK1A specifically interacts with and phosphorylates SEPT4. Phosphorylation of SEPT4 by DYRK1A was inhibited by harmine, which has recently been identified as the most specific inhibitor of DYRK1A. In support of a physiological relation in the brain, we found that Dyrk1A and Sept4 are co-expressed and co-localized in neocortical neurons. These findings suggest that SEPT4 is a substrate of DYRK1A kinase and thus provide a possible link for the involvement of DYRK1A in neurodegenerative processes and in DS neuropathologies.
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PMID:The Down syndrome candidate dual-specificity tyrosine phosphorylation-regulated kinase 1A phosphorylates the neurodegeneration-related septin 4. 1893 27

Cytoskeletal polymers are component of cellular infrastructure that are required for fundamental biological processes ranging from cell division to brain functions. Unlike the knowledge available for tubulin and actin, our understanding of unconventional cytoskeletal structures composed of GTP-binding proteins belonging to the septin family is limited, despite their ubiquity and implications in human diseases. Recent studies have revealed that septin plays unique modulatory roles as an accessory component of microtubules and the actin cytoskeleton. Morphological analyses of the mammalian brain and neural cells have revealed that septins preferentially cluster beneath the extra-synaptic membrane domains in dendritic shafts and spine necks, presynaptic terminals of major neurons, and astroglial processes. Live imaging analysis revealed that septin polymers are remarkably stable in these clusters, which may serve as local cytoskeleton and/or scaffold for the organization of specialized cortical domains in neurons and glia. This hypothesis has been supported by the hypo-dopaminergic phenotype of mice that lack the Sept4 subunit and the hyper-dopaminergic phenotype of those with excess Sept4. In these cases, the septin scaffold in the dopamine neurons is considered as a determinant of the quantity of a subset of presynaptic molecules, including tSNAREs (membrane-fusion machinery) and the dopamine transporters. This finding in mouse models is in agreement with the recent findings that qualitative and/or quantitative dysregulation of septins is involved in neurodegenerative disorders such as Parkinson disease and psychological disorders such as schizophrenia and bipolar disorder. Studies on tubulin/actin indicate that a better understanding of the septin family of proteins will improve our insight into neuropathological phenomena in neurodegenerative and psychological disorders, which may help develop diagnostic markers and therapeutic strategies for such diseases.
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PMID:[Functions of the septin cytoskeleton and its roles in dopaminergic neurotransmission]. 1937 12


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