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)

The understanding of the molecular mechanisms underlying Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy has made significant progress in the recent years. Lewy body appears to be principally made of alpha-synuclein, a presynaptic protein. It also contains ubiquitin and some components of the proteasome: this suggests that alteration of protein catabolism may be involved in its formation. In favor of this hypothesis, it should be noted that Parkin, a protein that is mutated in autosomal recessive Parkinson disease, is a ubiquitin ligase. Immunohistochemistry has shown that alpha-synuclein accumulates not only in the cell body of the neurones (Lewy body) but also in their processes (Lewy neurites); it has emphasized the severity of the pathology in the nucleus basalis of Meynert, amygdala, CA2-3 sector of the hippocampus and cerebral cortex. Cortical Lewy bodies are not considered any more the marker of dementia with Lewy bodies: they are, indeed, found in true Parkinson disease cases. In progressive supranuclear palsy, 4 repeats tau accumulates in the cytoplasm of neurones and glia. At electron microscopy, the accumulation is made of straight filaments. It involves not only the neurones (where it is the main constituent of the neurofibrillary tangles) but also the glia. Astrocytic tuft is to day considered the morphological marker of progressive supranuclear palsy. Tau protein accumulates in the cell body of the oligodendrocyte as a "coiled body"; the protein is also integrated in the myelin sheath, when the cytoplasm of the oligodendrocyte wraps around the axon. This explains the numerous "threads" that are visible in cases of progressive supranuclear palsy. Striato-nigral degeneration, sporadic olivo-ponto-cerebellar atrophy and primitive orthostatic hypotension are various clinico-pathologic aspects of the same disorder: multiple system atrophy. It is also characterized by a morphological marker: the accumulation of alpha-synuclein in the cytoplasm of glial cells, particularly oligodendrocytes. The term synucleinopathy has been proposed to describe both idiopathic Parkinson disease and multiple system atrophy. The reason explaining the cellular topography of alpha-synuclein accumulation, neuronal in Parkinson disease, glial in multiple system atrophy is still unknown.
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PMID:[Recent neuropathology of parkinsonian syndromes]. 1277 83

Parkinson's disease (PD) is a severe neurological disorder, characterized by the progressive degeneration of the dopaminergic nigrostriatal pathway and the presence of Lewy bodies (LBs). The discovery of genes responsible for familial forms of the disease has provided insights into its pathogenesis. Mutations in the parkin gene, which encodes an E3 ubiquitin-protein ligase involved in the ubiquitylation and proteasomal degradation of specific protein substrates, have been found in nearly 50% of patients with autosomal-recessive early-onset parkinsonism. The abnormal accumulation of substrates due to loss of Parkin function may be the cause of neurodegeneration in parkin-related parkinsonism. Here, we demonstrate that Parkin interacts with, ubiquitylates and promotes the degradation of p38, a key structural component of the mammalian aminoacyl-tRNA synthetase complex. We found that the ubiquitylation of p38 is abrogated by truncated variants of Parkin lacking essential functional domains, but not by the pathogenic Lys161Asn point mutant. Expression of p38 in COS7 cells resulted in the formation of aggresome-like inclusions in which Parkin was systematically sequestered. In the human dopaminergic neuroblastoma-derived SH-SY5Y cell line, Parkin promoted the formation of ubiquitylated p38-positive inclusions. Moreover, the overexpression of p38 in SH-SY5Y cells caused significant cell death against which Parkin provided protection. Analysis of p38 expression in the human adult midbrain revealed strong immunoreactivity in normal dopaminergic neurons and the labeling of LBs in idiopathic PD. This suggests that p38 plays a role in the pathogenesis of PD, opening the way for a detailed examination of its potential non-canonical role in neurodegeneration.
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PMID:The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration. 1278 50

Parkin is an E3 ligase that plays an important role in the ubiquitin/proteosome pathway responsible for protein degradation events. Mutations in parkin result in a loss-of-function and lead to Parkinson's disease, a progressive neurological disorder of movement. Presumably, this occurs due to the toxic build-up of proteins that are no longer effectively cleared/degraded by the parkin-dependent ubiqutin/proteosome pathway. To date, three types of proteins have been shown to interact with parkin. Firstly, the E2 ubiquitin conjugating proteins called UbcH7 and UbcH8 interact with parkin. Secondly, putative substrates interacting with parkin include a synaptic vesicle associated GTPase named CDCrel-1; a G protein-coupled receptor named Pael; a novel from of alpha-synuclein; and an alpha-synuclein interacting protein synphilin-1. Thirdly and more recently, a PDZ domain containing scaffolding protein CASK/Lin2 has been shown to interact with the PDZ binding motif of parkin. A network of PDZ-interacting proteins has potential to form a complex web of molecules that surround parkin and regulate its subcellular localisation and function.
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PMID:Part I: parkin-associated proteins and Parkinson's disease. 1281 56

Parkinson's disease is characterized by the progressive and selective loss of the dopaminergic neurons in the substantia nigra and the presence of ubiquitinated protein inclusions termed Lewy bodies. In the past six years, four genes involved in rare inherited forms of Parkinson's disease have been identified: mutations in the alpha-synuclein and ubiquitin carboxyterminal hydrolase L1 genes (UCH-L1) cause autosomal dominant forms, whereas mutations in the Parkin and DJ-1 genes are responsible for autosomal recessive forms of the disease. A toxic gain of function related to the ability of alpha-synuclein to assemble into insoluble amyloid fibrils may underlie neuronal cell death in parkinsonism due to alpha-synuclein gene mutations. In contrast, loss of protein function appears to be the cause of the disease in parkinsonism due to mutations in the genes encoding Parkin and UCH-L1, which are key enzymes of the ubiquitin-proteasome pathway. The presence of alpha-synuclein, Parkin and UCH-L1 in Lewy bodies suggests that dysfunction of pathways involved in protein folding and degradation is not only involved in the pathogenesis of familial Parkinson's disease, but could also play a role in the frequent sporadic form of the disease (idiopathic Parkinson's disease).
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PMID:[Parkinson's disease: what have we learned from the genes responsible for familial forms?]. 1283 96

Mutations in parkin cause Parkinson's disease due to the loss of the ubiquitin-protein ligase activity of Parkin protein. Recent data suggest we may be beginning to understand the nature of the proteins that are targeted by Parkin and how these cause neuronal damage.
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PMID:Neurodegeneration: how does parkin prevent Parkinson's disease? 1284 30

Autosomal-recessive juvenile parkinsonism (AR-JP) is caused by mutations in the parkin gene. Parkin protein is characterized by a ubiquitin-like domain at its NH(2) terminus and by two RING finger motifs and one IBR (in between RING finger) motif at its COOH-terminus (RING-IBR-RING). We showed that the parkin protein is an E3 ubiquitin ligase, which binds to ubiquitin-conjugating enzymes (E2s) through its RING-IBR-RING motif. The pathogenesis of AR-JP, therefore, was hypothesized to be accumulation of unidentified neurotoxic protein (a substrate of parkin). On the basis of this hypothesis, the substrate of parkin was sought using a yeast two-hybrid system. A putative G protein-coupled transmembrane polypeptide, named Pael (parkin-associated endothelin receptor-like) receptor, was identified as a parkin binding protein. When overexpressed in cells, this receptor tends to become unfolded, insoluble, and ubiquitinated. The insoluble Pael receptor leads to endoplasmic reticulum (ER) stress-induced cell death. Parkin specifically ubiquitinates this receptor in the presence of ER-resident E2s and promotes the degradation of unfolded Pael receptor, resulting in suppression of the cell death induced by the accumulation of unfolded Pael receptor in the ER. Moreover, the insoluble form of Pael receptor accumulates in the brain of AR-JP patients. This protein is highly expressed in the dopaminergic neurons in the substantia nigra, which is specifically affected in Parkinson's disease; although it is also widely expressed in oligodendroglias in the fiber tract. In conclusion, we showed that the accumulation of unfolded Pael receptor (a substrate of parkin) may cause selective death of dopaminergic neurons in AR-JP.
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PMID:Parkin and endoplasmic reticulum stress. 1284 78

Accumulation and toxic conversion to protofibrils of alpha-synuclein has been associated with neurological disorders such as Parkinson's disease (PD), Lewy body disease, multiple system atrophy, neurodegeneration with brain iron accumulation type 1, and Alzheimer's disease. In recent years, modeling these disorders in transgenic (tg) mice and flies has helped improve understanding of the pathogenesis of these diseases and has established the basis for the development of new experimental treatments. Overexpression of alpha-synuclein in tg mice in a region- and cell-specific manner results in degeneration of selective circuitries accompanied by motor deficits and inclusion formation similar to what is found in PD and related disorders. Furthermore, studies in singly and doubly tg mice have shown that toxic conversion and accumulation can be accelerated by alpha-synuclein mutations associated with familial parkinsonism, by amyloid beta peptide 1-42 (Abeta 1-42), and by oxidative stress. In contrast, molecular chaperones such as Hsp70 and close homologues such as alpha-synuclein have been shown to suppress toxicity. Similar studies are underway to evaluate the effects of other modifying genes that might play a role in alpha-synuclein ubiquitination. Among them considerable interest has been placed on the role of molecules associated with familial parkinsonism (Parkin, UCHL-1). Furthermore, studying the targeted overexpression of alpha-synuclein and other modifier genes in the nigrostriatal and limbic system by using regulatable promoters, lentiviral vectors, and siRNA will help improve understanding of the molecular mechanisms involved in selective neuronal vulnerability, and it will aid the development of new treatments.
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PMID:Transgenic models of alpha-synuclein pathology: past, present, and future. 1284 86

Inactivating mutations of the gene encoding parkin are responsible for some forms of autosomal recessive juvenile Parkinson disease. Parkin is a ubiquitin ligase that ubiquitinates misfolded proteins targeted for the proteasome-dependent protein degradation pathway. Using the yeast two-hybrid system and co-immunoprecipitation methods, we identified synaptotagmin XI as a protein that interacts with parkin. Parkin binds to the C2A and C2B domains of synaptotagmin XI resulting in the polyubiquitination of synaptotagmin XI. Truncated and missense mutated parkins reduce parkin-sytXI binding affinity and ubiquitination. Parkin-mediated ubiquitination also enhances the turnover of sytXI. In sporadic PD brain sections, sytXI was found in the core of the Lewy bodies. Since synaptotagmin XI is a member of the synaptotagmin family that is well characterized in their importance for vesicle formation and docking, the interaction with this protein suggests a role for parkin in the regulation of the synaptic vesicle pool and in vesicle release. Loss of parkin could thus affect multiple proteins controlling vesicle pools, docking and release and explain the deficits in dopaminergic function seen in patients with parkin mutations.
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PMID:The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XI. 1292 69

Parkin is a protein-ubiquitin E3 ligase linked to Parkinson's disease. Although several substrates of parkin have been identified, the subcellular location for parkin to recognize and ubiquitinate its targets is unclear. Here we report that parkin was accumulated in the centrosome when SH-SY5Y or transfected HEK293 cells were treated with the proteasome inhibitor lactacystin. The specific recruitment of parkin was dependent on concentration and duration of the treatment, and was accompanied by the centrosomal accumulation of ubiquitinated proteins and CDCrel-1, a substrate of parkin. The recruitment of parkin was apparently mediated through its binding to gamma-tubulin, which has been shown to accumulate in the centrosome in response to misfolded proteins. Furthermore, the effect was abrogated by the microtubule-depolymerizing drug colchicine or the microtubule-stabilizing drug taxol, which indicates that the intact microtubule network is required for the centrosomal recruitment of parkin. Taken together, our data suggest that the lactacystin-induced accumulation of parkin in the centrosome plays a significant role in the ubiquitination of misfolded substrates accumulated there. This process may provide a subcellular locale for parkin to ubiquitinate and degrade protein aggregates critically involved in the pathogenesis of Parkinson's disease.
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PMID:Parkin is recruited to the centrosome in response to inhibition of proteasomes. 1292 31

Loss-of-function mutations in parkin are the major cause of early-onset familial Parkinson's disease. To investigate the pathogenic mechanism by which loss of parkin function causes Parkinson's disease, we generated a mouse model bearing a germline disruption in parkin. Parkin-/- mice are viable and exhibit grossly normal brain morphology. Quantitative in vivo microdialysis revealed an increase in extracellular dopamine concentration in the striatum of parkin-/- mice. Intracellular recordings of medium-sized striatal spiny neurons showed that greater currents are required to induce synaptic responses, suggesting a reduction in synaptic excitability in the absence of parkin. Furthermore, parkin-/- mice exhibit deficits in behavioral paradigms sensitive to dysfunction of the nigrostriatal pathway. The number of dopaminergic neurons in the substantia nigra of parkin-/- mice, however, is normal up to the age of 24 months, in contrast to the substantial loss of nigral neurons characteristic of Parkinson's disease. Steady-state levels of CDCrel-1, synphilin-1, and alpha-synuclein, which were identified previously as substrates of the E3 ubiquitin ligase activity of parkin, are unaltered in parkin-/- brains. Together these findings provide the first evidence for a novel role of parkin in dopamine regulation and nigrostriatal function, and a non-essential role of parkin in the survival of nigral neurons in mice.
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PMID:Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. 1293 Aug 22


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