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 Leucine-rich repeat kinase 2 (LRRK2) are linked to the most common familial forms and some sporadic forms of Parkinson's disease (PD). The LRRK2 protein contains two well-known functional domains, MAPKKK-like kinase and Rab-like GTPase domains. Emerging evidence shows that LRRK2 contains kinase activity which is enhanced in several PD-associated mutants of LRRK2. However, the GTPase activity of LRRK2 has yet to be formally demonstrated. Here, we produced and purified the epitope-tagged LRRK2 protein from transgenic mouse brain, and showed that purified brain LRRK2 possesses both kinase and GTPase activity as assayed by GTP binding and hydrolysis. The brain LRRK2 is associated with elevated kinase activity in comparison to that from transgenic lung or transfected cultured cells. In transfected cell cultures, we detected GTP hydrolysis activity in full-length as well as in GTPase domain of LRRK2. This result indicates that LRRK2 GTPase can be active independent of LRRK2 kinase activity (while LRRK2 kinase activity requires the presence of LRRK2 GTPase as previously shown). We further found that PD mutation R1441C/G in the GTPase domain causes reduced GTP hydrolysis activity, consistent with the altered enzymatic activity in the mutant LRRK2 carrying PD familial mutations. Therefore, our study shows the biochemical characteristics of brain-specific LRRK2 which is associated with robust kinase and GTPase activity. The distinctive levels of kinase/GTPase activity in brain LRRK2 may help explain LRRK2-associated neuronal functions or dysfunctions in the pathogenesis of PD.
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PMID:Leucine-rich repeat kinase 2 (LRRK2)/PARK8 possesses GTPase activity that is altered in familial Parkinson's disease R1441C/G mutants. 1762 48

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the leading cause of autosomal dominant Parkinson's disease (PD). LRRK2, a member of the ROCO protein family, contains both Ras GTPase-like (Roc) and kinase (MAPKKK) domains, as well as other functional motifs. Here, we have identified LRRK2 as the first mammalian ROCO protein that is an authentic and functional GTPase, defined by the ability to bind GTP and undergo intrinsic GTP hydrolysis. Furthermore, the Roc domain is sufficient for this native GTPase activity and binds and hydrolyzes GTP indistinguishably from the Ras-related small GTPase, Rac1. The PD-associated mutation, R1441C, located within the Roc domain, leads to an increase in LRRK2 kinase activity and a decrease in the rate of GTP hydrolysis, compared to the wild-type protein, in an in vitro assay. This finding suggests that the R1441C mutation may help stabilize an activated state of LRRK2. Additionally, LRRK2-mediated phosphorylation is stimulated upon binding of non-hydrolyzable GTP analogs, suggesting that LRRK2 is an MAPKKK-activated intramolecularly by its own GTPase. Since GTPases and MAPKKKs are upstream regulators of multiple signal transduction cascades, LRRK2 may play a central role in integrating pathways involved in neuronal cell signaling and the pathogenesis of PD.
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PMID:The Parkinson's disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase that stimulates kinase activity. 1770 65

Memantine is reported to improve symptoms in moderate cases of Alzheimer's disease and Parkinson's disease, but is also known to trigger psychosis in some Parkinson patients. Because these clinical features suggested a possible dopamine component of memantine action, we measured the potency of memantine on the functional high-affinity state of dopamine D2 receptors, or D2(High). Using [(3)H]domperidone to label D2 receptors, the memantine dissociation constant at D2(High) was 917 +/- 23 nM for rat striatal D2 receptors and 137 +/- 19 nM for human cloned D2Long receptors. The memantine dissociation constant for striatal N-methyl-D-aspartate (NMDA) receptors labeled by [(3)H]MK 801 was 2200 +/- 400 nM. Memantine stimulated the incorporation of [(35)S]GTP-gamma-S into D2-expressing Chinese Hamster Ovary cells with a dissociation constant of 1200 +/- 400 nM. Memantine, between 200 and 2000 nM, directly acted on D2(High) to inhibit the release of prolactin from isolated anterior pituitary cells in culture. Because the memantine potencies at NMDA receptors and dopamine D2(High) receptors are of a similar order of magnitude, it is likely that the clinical features of memantine can be attributed to its action at both types of receptors.
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PMID:Memantine agonist action at dopamine D2High receptors. 1800 Aug 14

(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for aromatic amino acid hydroxylases, such as phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH), tryptophan hydroxylase, and nitric oxide synthase, which catalyze physiologically important reactions in mammals. The biosynthesis and metabolism of BH4 is usually studied mostly in the liver and only slightly in the brain, as the BH4 level in the liver is relatively high because BH4 is required for the reaction of PAH. We found that GTP (guanosine triphosphate) cyclohydrolase I, an enzyme for the biosynthesis of BH4, is a causative gene for DOPA (3,4-dihydroxyphenylalanine)-responsive dystonia (also called Segawa's disease), and that partial deficiency of BH4 leads to the dysfunction of the nigrostriatal dopaminergic neurons without hyperphenylalaninemia. We analyzed BH4-deficient mice that were produced by disruption of a BH4-synthesizing gene by a gene-knockout technique. We found that the protein amount of TH was highly dependent on the amount of BH4, especially in nerve terminals. Our research suggests that BH4 metabolism in the brain should be different from that in the liver, and that altered metabolism of BH4 should lead to neuropsychiatric disorders including Parkinson's disease.
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PMID:Metabolism of tetrahydrobiopterin: its relevance in monoaminergic neurons and neurological disorders. 1910 67

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

Mutations in the gene encoding LRRK2 (leucine-rich repeat kinase 2) were first identified in 2004 and have since been shown to be the single most common cause of inherited Parkinson's disease. The protein is a large GTP-regulated serine/threonine kinase that additionally contains several protein-protein interaction domains. In the present review, we discuss three important, but unresolved, questions concerning LRRK2. We first ask: what is the normal function of LRRK2? Related to this, we discuss the evidence of LRRK2 activity as a GTPase and as a kinase and the available data on protein-protein interactions. Next we raise the question of how mutations affect LRRK2 function, focusing on some slightly controversial results related to the kinase activity of the protein in a variety of in vitro systems. Finally, we discuss what the possible mechanisms are for LRRK2-mediated neurotoxicity, in the context of known activities of the protein.
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PMID:Leucine-rich repeat kinase 2 mutations and Parkinson's disease: three questions. 1957 25

Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common cause of autosomal-dominant familial and late-onset sporadic Parkinson's disease (PD). LRRK2 is a large multi-domain protein featuring a GTP-binding C-terminal of Ras of complex proteins (ROC) (ROCO) domain combination unique for the ROCO protein family, directly followed by a kinase domain. Dimerization is a well-established phenomenon among protein kinases. Here, we confirm LRRK2 self-interaction, and provide evidence for general homo- and heterodimerization potential among the ROCO kinase family (LRRK2, LRRK1, and death-associated protein kinase 1). The ROCO domain was critically, though not exclusively involved in dimerization, as a LRRK2 deletion mutant lacking the ROCO domain retained dimeric properties. GTP binding did not appear to influence ROCO(LRRK2) self-interaction. Interestingly, ROCO(LRRK2) fragments exerted an inhibitory effect on both wild-type and the elevated G2019S LRRK2 autophosphorylation activity. Insertion of PD mutations into ROCO(LRRK2) reduced self-interaction and led to a reduction of LRRK2 kinase inhibition. Collectively, these results suggest a functional link between ROCO interactions and kinase activity of wild-type and mutant LRRK2. Importantly, our finding of ROCO(LRRK2) fragment-mediated LRRK2 kinase inhibition offers a novel lead for drug design and thus might have important implications for new therapeutic avenues in PD.
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PMID:Homo- and heterodimerization of ROCO kinases: LRRK2 kinase inhibition by the LRRK2 ROCO fragment. 1971 61

Mutations in GTP-cyclohydrolase 1 (GCH1) cause autosomal dominant dopa-responsive dystonia (DRD), characterized by childhood-onset foot dystonia that later generalizes. DRD patients frequently present with associated Parkinsonism. Conversely, early-onset Parkinson's disease (EOPD) patients commonly display dystonia. Herein, we investigated the frequency of GCH1 mutations in a series of 53 familial EOPD patients (21 with dystonia) and screened them for mutations in PRKN, PINK1, and DJ-1. In addition, we examined a matched EOPD patient-control series for association of common variability at the GCH1 locus and EOPD susceptibility. No GCH1 coding change or copy-number abnormality was identified in familial EOPD patients. A novel 18-bp deletion was found in the proximal promoter (two patients, one control), which is expected to knock out two regulatory elements previously shown to regulate GCH1 transcription. No association was found between GCH1 variability and risk of EOPD. Fourteen (26.4%) familial EOPD patients had homozygous or compound heterozygous PRKN mutations. PRKN-positive patients were 10 years younger than PRKN-negative patients and had a twofold higher prevalence of dystonia. This study does not support a significant role for genetic variation at the GCH1 locus in EOPD. However, our results further highlight the relevance of PRKN screening in familial EOPD.
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PMID:GCH1 in early-onset Parkinson's disease. 1973 94

LRRK2 is a 250 kDa multidomain protein, mutations in which cause familial Parkinson's disease. Previously, we have demonstrated that the R1441C mutation in the ROC domain decreases GTPase activity. Here we show that the R1441C alters the folding properties of the ROC domain, lowering its thermodynamic stability. Similar to small GTPases, binding of different guanosine nucleotides alters the stability of the ROC domain, suggesting that there is an alteration in conformation dependent on GDP or GTP occupying the active site. GTP/GDP bound state also alters the self-interaction of the ROC domain, accentuating the impact of the R1441C mutation on this property. These data suggest a mechanism whereby the R1441C mutation can reduce the GTPase activity of LRRK2, and highlights the possibility of targeting the stability of the ROC domain as a therapeutic avenue in LRRK2 disease.
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PMID:The R1441C mutation alters the folding properties of the ROC domain of LRRK2. 1978 41

Dominant missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known genetic cause of Parkinson disease. LRRK2 encodes a serine/threonine protein kinase, and pathogenic mutations may increase kinase activity. Intrinsic GTP binding in the GTPase domain may govern kinase activity through an internal signal transduction cascade. As with many protein kinases, LRRK2 self-interacts through mechanisms that may regulate enzymatic activity. We find that the disruption of either GTPase or kinase activity enhances the formation of high molecular weight oligomers and prevents the formation of LRRK2 dimer structures. In addition, brief application of the broad spectrum kinase inhibitor staurosporine ablates LRRK2 dimers and promotes LRRK2 high molecular weight oligomers. LRRK2 interactions with other proteins in cell lines are kinase-independent and include chaperones and cell cytoskeleton components, suggesting that LRRK2 self-assembly principally dictates complex size. To further explore the mechanics of kinase activation, we separate soluble LRRK2 protein that encodes the pathogenic G2019S mutation into high molecular weight oligomers, dimers, and monomers and find that kinase activity resides with dimeric LRRK2. Some PD-associated mutations that increase kinase activity in vitro significantly increase the proportion of dimer structures relative to total LRRK2 protein, providing additional insight into how pathogenic mutations may alter normal enzymatic regulation. Targeting and tracking LRRK2 dimerization may provide a clear way to observe LRRK2 kinase activity in living cells, and disruption of dimeric LRRK2 through kinase inhibition or other means may attenuate pathogenic increases in LRRK2 enzymatic output.
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PMID:Dependence of leucine-rich repeat kinase 2 (LRRK2) kinase activity on dimerization. 1982 9


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