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)

Protease-activated receptor-2 (PAR-2) is a G protein-coupled receptor activated by trypsin and other trypsin-like serine proteases. The widely expressed PAR-2 is involved in inflammation response but the physiological/pathological roles of PAR-2 in the nervous system are still uncertain. In the present study, we report novel PAR-2 interaction proteins, alphaA-crystallin and alphaB-crystallin. These 20 kDa proteins have been implicated in neurodegenerative diseases like Alexander's disease, Creutzfeldt-Jacob disease, Alzheimer's disease, and Parkinson's disease. Results from yeast two-hybrid assay using the cytoplasmic C-tail of PAR-2 as bait suggested that alphaA-crystallin interacts with PAR-2. We further demonstrate the in vitro and cellular in vivo interaction of C-tail of PAR-2 as well as of full-length PAR-2 with alphaA(alphaB)-crystallins. We use pull-down, co-immunoprecipitation, and co-localization assays. Analysis of alphaA-crystallin deletion mutants showed that amino acids 120-130 and 136-154 of alphaA-crystallin are required for the interaction with PAR-2. Co-immunoprecipitation experiments ruled out an interaction of alphaA(alphaB)-crystallins with PAR-1, PAR-3, and PAR-4. This demonstrates that alphaA(alphaB)-crystallins are PAR-2-specific interaction proteins. Moreover, we investigated the functional role of PAR-2 and alpha-crystallins in astrocytes. Evidence is presented to show that PAR-2 activation and increased expression of alpha-crystallins reduced C2-ceramide- and staurosporine-induced cell death in astrocytes. Thus, both PAR-2 and alpha-crystallins are involved in cytoprotection in astrocytes.
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PMID:Alpha A-crystallin and alpha B-crystallin, newly identified interaction proteins of protease-activated receptor-2, rescue astrocytes from C2-ceramide- and staurosporine-induced cell death. 1955 54

Mutations in the alpha synuclein gene (SNCA) are the most potent cause of autosomal dominant Parkinson disease (PD) while mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause. We hypothesized that a direct interaction may exist between their protein products. Here we show that full-length Lrrk2 or fragments containing its kinase domain have a significant capacity to phosphorylate recombinant alpha synuclein (Asyn) at serine 129. Such phosphorylated Asyn is the major component of pathological deposits in PD. We further show that the G2019S mutation in Lrrk2, which is the most common genetic determinant of PD, has a significantly greater capacity than wild-type Lrrk2 to phosphorylate Asyn. This suggests that the G2019S mutant protein may cause PD by generating pathological levels of phosphorylated Asyn. Controlling Lrrk2 Asyn phosphokinase activity may be an approach to disease modifying therapy for PD and other synucleinopathies.
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PMID:Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications. 1957 76

In synucleinopathies, including Parkinson's disease, partially ubiquitylated alpha-synuclein species phosphorylated on serine 129 (P(S129)-alpha-synuclein) accumulate abnormally. Parkin, an ubiquitin-protein ligase that is dysfunctional in autosomal recessive parkinsonism, protects against alpha-synuclein-mediated toxicity in various models.We analyzed the effects of Parkin deficiency in a mouse model of synucleinopathy to explore the possibility that Parkin and alpha-synuclein act in the same biochemical pathway. Whether or not Parkin was present, these mice developed an age-dependent neurodegenerative disorder preceded by a progressive decline in performance in tasks predictive of sensorimotor dysfunction. The symptoms were accompanied by the deposition of P(S129)-alpha-synuclein but not P(S87)-alpha-synuclein in neuronal cell bodies and neuritic processes throughout the brainstem and the spinal cord; activation of caspase 9 was observed in 5% of the P(S129)-alpha-synuclein-positive neurons. As in Lewy bodies, ubiquitin-immunoreactivity, albeit less abundant, was invariably co-localized with P(S129)-alpha-synuclein. During late disease stages, the disease-specific neuropathological features revealed by ubiquitin- and P(S129)-alpha-synuclein-specific antibodies were similar in mice with or without Parkin. However, the proportion of P(S129)-alpha-synuclein-immunoreactive neuronal cell bodies and neurites co-stained for ubiquitin was lower in the absence than in the presence of Parkin, suggesting less advanced synucleinopathy. Moreover, sensorimotor impairment and manifestation of the neurodegenerative phenotype due to overproduction of human alpha-synuclein were significantly delayed in Parkin-deficient mice.These findings raise the possibility that effective compensatory mechanisms modulate the phenotypic expression of disease in parkin-related parkinsonism.
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PMID:Parkin deficiency delays motor decline and disease manifestation in a mouse model of synucleinopathy. 1968 May 61

The LRRK2 (leucine-rich repeat protein kinase-2) is mutated in a significant number of Parkinson's disease patients, but little is known about its regulation and function. A common mutation changing Gly2019 to serine enhances catalytic activity, suggesting that small-molecule inhibitors might have utility in treating Parkinson's disease. We employed various approaches to explore the substrate-specificity requirements of LRRK2 and elaborated a peptide substrate termed Nictide, that had 20-fold lower Km and nearly 2-fold higher Vmax than the widely deployed LRRKtide substrate. We demonstrate that LRRK2 has marked preference for phosphorylating threonine over serine. We also observed that several ROCK (Rho kinase) inhibitors such as Y-27632 and H-1152, suppressed LRRK2 with similar potency to which they inhibited ROCK2. In contrast, GSK429286A, a selective ROCK inhibitor, did not significantly inhibit LRRK2. We also identified a mutant LRRK2[A2016T] that was normally active, but resistant to H-1152 and Y-27632, as well as sunitinib, a structurally unrelated multikinase inhibitor that, in contrast with other compounds, suppresses LRRK2, but not ROCK. We have also developed the first sensitive antibody that enables measurement of endogenous LRRK2 protein levels and kinase activity as well as shRNA (short hairpin RNA) methods to reduce LRRK2 expression. Finally, we describe a pharmacological approach to validate whether substrates are phosphorylated by LRRK2 and use this to provide evidence that LRRK2 may not be rate-limiting for the phosphorylation of the proposed substrate moesin. The findings of the present study will aid with the investigation of LRRK2.
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PMID:Substrate specificity and inhibitors of LRRK2, a protein kinase mutated in Parkinson's disease. 1974 74

Dopamine depletion leads to impaired motor performance and increased glutamatergic-mediated hyperexcitability of medium spiny neurons in the basal ganglia. Intensive treadmill exercise improves motor performance in both saline treatment and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. In the present study, we investigated the effect of high-intensity treadmill exercise on changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit expression, because these receptor channels confer the majority of fast excitatory neurotransmission in the brain, and their subunit composition provides a key mechanism for regulating synaptic strength and synaptic neuroplasticity and is important in modulating glutamatergic neurotransmission. Within the dorsolateral striatum of MPTP mice, treadmill exercise increased GluR2 subunit expression, with no significant effect on GluR1. Furthermore, neurophysiological studies demonstrated a reduction in the size of excitatory postsynaptic currents (EPSCs) in striatal medium spiny neurons (as determined by the input-output relationship), reduced amplitude of spontaneous EPSCs, and a loss of polyamine-sensitive inward rectification, all supportive of an increase in heteromeric AMPAR channels containing the GluR2 subunit. Phosphorylation of GluR2 at serine 880 in both saline-treated and MPTP mice suggests that exercise may also influence AMPAR trafficking and thus synaptic strength within the striatum. Finally, treadmill exercise also altered flip isoforms of GluR2 and GluR1 mRNA transcripts. These findings suggest a role for AMPARs in mediating the beneficial effects of exercise and support the idea that adaptive changes in GluR2 subunit expression may be important in modulating experience-dependent neuroplasticity of the injured basal ganglia.
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PMID:Altered AMPA receptor expression with treadmill exercise in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury. 1974 27

Mutations in the neuronal protein alpha-synuclein cause familial Parkinson disease. Phosphorylation of alpha-synuclein at serine 129 is prominent in Parkinson disease and influences alpha-synuclein neurotoxicity. Here we report that alpha-synuclein is also phosphorylated at tyrosine 125 in transgenic Drosophila expressing wild-type human alpha-synuclein and that this tyrosine phosphorylation protects from alpha-synuclein neurotoxicity in a Drosophila model of Parkinson disease. Western blot analysis of fly brain homogenates showed that levels of soluble oligomeric species of alpha-synuclein were increased by phosphorylation at serine 129 and decreased by tyrosine 125 phosphorylation. Tyrosine 125 phosphorylation diminished during the normal aging process in both humans and flies. Notably, cortical tissue from patients with the Parkinson disease-related synucleinopathy dementia with Lewy bodies showed less phosphorylation at tyrosine 125. Our findings suggest that alpha-synuclein neurotoxicity in Parkinson disease and related synucleinopathies may result from an imbalance between the detrimental, oligomer-promoting effect of serine 129 phosphorylation and a neuroprotective action of tyrosine 125 phosphorylation that inhibits toxic oligomer formation.
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PMID:Tyrosine and serine phosphorylation of alpha-synuclein have opposing effects on neurotoxicity and soluble oligomer formation. 1985 33

The toxicity caused by cell exposure to 1-methyl-4-phenylpyridinium ion (MPP(+)) is a useful model in the study of Parkinson's disease (PD). However, the exact molecular mechanisms triggered by MPP(+) in cell death are currently unclear. In the present research, we show that exposure to MPP(+) induce the cell death of neuroblastoma-derived dopaminergic B65 cells, which is not reversed by the widely known caspase inhibitor Z-VAD fmk or by calpain inhibition. Likewise, when B65 cells were treated with MPP(+), the DNA damage pathway that involves p53 was activated, and cells were arrested in the G(2)/M phase of the cell cycle. Interestingly, MPP(+) has two effects on the expression of cell cycle-related proteins. It increases the content of cyclins A, E, cdk2 and the phosphorylated form of pRb (serine 780). However, MPP(+) 5mM decreased the expression of cyclin D1, B1 and cdk4. The decrease in the expression of cyclin B1 may be related to the arrest of cells observed in the G(2)/M phase of cell cycle. The increase in S phase cell cycle proteins and retinoblastoma protein phosphorylation was an unexpected result. As the antioxidant trolox attenuated the process of cell loss and changes in the cell cycle, as measured by flow cytometry, we concluded that oxidative stress was involved in the effects of MPP(+) in this cell line. In summary, the present work characterizes the molecular changes involved in damage caused by MPP(+) in B65 cells, and highlights the effects of MPP(+) on molecules involved in the control of cell cycle progression.
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PMID:Effects of MPP+ on the molecular pathways involved in cell cycle control in B65 neuroblastoma cells. 2008 Jan 85

Mutations in leucine-rich repeat kinase 2 (LRRK2) that increase its kinase activity associate with familial forms of Parkinson disease (PD). As phosphorylation determines the functional state of most protein kinases, we systematically mapped LRRK2 phosphorylation sites by mass spectrometry. Our analysis revealed a high degree of constitutive phosphorylation in a narrow serine-rich region preceding the LRR-domain. Allowing de novo autophosphorylation of purified LRRK2 in an in vitro autokinase assay prior to mass spectrometric analysis, we discovered multiple sites of autophosphorylation. Solely serine and threonine residues were found phosphorylated suggesting LRRK2 as a true serine threonine kinase. Autophosphorylation mainly targets the ROC GTPase domain and its clustering around the GTP binding pocket of ROC suggests cross-regulatory activity between kinase and Roc domain. In conclusion, the phosphoprotein LRRK2 functions as an autocatalytically active serine threonine kinase. Clustering of phosphosites within two discrete domains suggest that phosphorylation may regulate its biological functions in a yet unknown fashion.
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PMID:Phosphopeptide analysis reveals two discrete clusters of phosphorylation in the N-terminus and the Roc domain of the Parkinson-disease associated protein kinase LRRK2. 2010 44

Pin1 [Protein Interacting with NIMA (never in mitosis A)] is a peptidyl prolyl cis-trans isomerase that isomerizes phospho-Serine/Threonine-Proline [p(S/T)-P] motifs of its target proteins. Pin1 functions in concert with proline directed kinases such as cyclin-dependent protein kinases, extracellular signal-regulated kinases, and c-Jun N- terminal kinase, and protein phosphatases such as protein phosphatase 2A (PP2A) and PP2B, in the regulation of a wide range of cellular processes including cell division, DNA damage response, and gene transcription, and in susceptibility to cancer and neurodegenerative diseases. This review focuses on the roles of Pin1 in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Frontotemporal dementia associated with parkinsonism linked to chromosome 17. Pin1 interacts with neuronal cytoskeletal proteins such as tau, amyloid-beta protein precursor, alpha-synuclein, and neurofilaments, often in association with phosphorylation events that influence their functions in the neuronal cytoskeleton. Overexpression of Pin1 reduces WT tau stability but increases P301L mutant tau stability. Pin1 associates with neurofilament H (NF-H) and modulates excitotoxic and oxidative stress induced perikaryal phosphorylation of NF-H. Pin1 mediates the neural specific apoptosis machinery. The specific inhibitors of Pin1 may have potential therapeutic implications in neurodegeneration.
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PMID:Phosphorylation-specific peptidyl-prolyl isomerization of neuronal cytoskeletal proteins by Pin1: implications for therapeutics in neurodegeneration. 2011 May 89

When cells are exposed to hyperosmotic stress, the Dictyostelium STAT orthologue STATc is rapidly tyrosine phosphorylated. Previous observations suggest a non-paradigmatic mode of STAT activation, whereby stress-induced serine phosphorylation of the PTP3 protein tyrosine phosphatase inhibits its activity towards STATc. We show that two serine residues in PTP3, S448 and S747, are rapidly phosphorylated after osmotic stress. cGMP is a second messenger for hyperosmotic stress response and 8-bromo-cGMP, a membrane-permeable form of cGMP, is a known activator of STATc. GbpC, a cGMP-binding Ras guanine nucleotide exchange factor protein, is a founder member of a protein family that includes LRRK2, the gene commonly mutated in familial Parkinson's disease. Genetic ablation of gbpC prevents STATc activation by 8-bromo-cGMP. However, osmotic-stress-induced activation of STATc occurs normally in the gbpC null mutant. Moreover, 8-bromo-cGMP does not stimulate phosphorylation of S448 and S747 of PTP3 in a wild-type strain. These facts imply the occurrence of redundant activation pathways. We present evidence that intracellular Ca(2+) is a parallel second messenger, by showing that agents that elevate intracellular Ca(2+) levels are potent STATc activators that stimulate phosphorylation of S448 and S747. We propose that stress-induced cGMP signalling exerts its stimulatory effect by potentiating the activity of a semi-constitutive tyrosine kinase that phosphorylates STATc, whereas parallel, stress-induced Ca(2+) signalling represses STATc dephosphorylation through its inhibitory effect on PTP3.
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PMID:Dual regulation of a Dictyostelium STAT by cGMP and Ca2+ signalling. 2015 63


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