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 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

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

The protein leucine-rich repeat kinase 2 (LRRK2) is a key player in the pathogenesis of Parkinson's disease (PD). Mutations in the LRRK2 gene account for up to 10% of all autosomal dominant forms of familiar and for approximately 1-3% of sporadic PD patients. Although the LRRK2 protein has many functional domains like a leucine-rich repeat domain, a Roc-GTPase domain, a kinase domain of the tyrosine kinase-like subfamily and multiple protein interaction domains (armadillo, ankyrin, WD40), the exact biological role of LRRK2 in the human brain is elusive. To gain more insight into the biological function of this protein, we monitored the changes in the expression profiles of SH-SY5Y cells, a dopaminergic neuroblastoma cell line, induced by a depletion of LRRK2 levels by RNA interference (RNAi) with Affymetrix U133 Plus 2.0 microarrays. A total of 187 genes were differentially regulated by at least a 1.5-fold change with 94 transcripts being upregulated and 93 transcripts being downregulated compared to scrambled control siRNA transfected cells. Key players of the interaction networks were independently verified by qRT-PCR. The differentially expressed gene products are involved in axonal guidance, nervous system development, cell cycle, cell growth, cell differentiation, cell communication, MAPKKK cascade, and Ras protein signal transduction. Defined gene expression networks will now serve to look more closely for candidates affected by LRRK2 reduction and how they might be altered in other forms of familial or sporadic PD.
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PMID:RNA interference of LRRK2-microarray expression analysis of a Parkinson's disease key player. 1809 93

Chronic L-dopa treatment of Parkinson's disease (PD) often leads to debilitating involuntary movements, termed L-dopa-induced dyskinesia (LID), mediated by dopamine (DA) receptors. RGS9-2 is a GTPase accelerating protein that inhibits DA D2 receptor-activated G proteins. Herein, we assess the functional role of RGS9-2 on LID. In monkeys, Western blot analysis of striatal extracts shows that RGS9-2 levels are not altered by MPTP-induced DA denervation and/or chronic L-dopa administration. In MPTP monkeys with LID, striatal RGS9-2 overexpression--achieved by viral vector injection into the striatum--diminishes the involuntary movement intensity without lessening the anti-parkinsonian effects of the D1/D2 receptor agonist L-dopa. In contrasts, in these animals, striatal RGS9-2 overexpression diminishes both the involuntary movement intensity and the anti-parkinsonian effects of the D2/D3 receptor agonist ropinirole. In unilaterally 6-OHDA-lesioned rats with LID, we show that the time course of viral vector-mediated striatal RGS9-2 overexpression parallels the time course of improvement of L-dopa-induced involuntary movements. We also find that unilateral 6-OHDA-lesioned RGS9-/- mice are more susceptible to L-dopa-induced involuntary movements than unilateral 6-OHDA-lesioned RGS9+/+ mice, albeit the rotational behavior--taken as an index of the anti-parkinsonian response--is similar between the two groups of mice. Together, these findings suggest that RGS9-2 plays a pivotal role in LID pathophysiology. However, the findings also suggest that increasing RGS9-2 expression and/or function in PD patients may only be a suitable therapeutic strategy to control involuntary movements induced by nonselective DA agonist such as L-dopa.
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PMID:RGS9-2 negatively modulates L-3,4-dihydroxyphenylalanine-induced dyskinesia in experimental Parkinson's disease. 1816 Jun 41

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the leading cause of genetically inherited Parkinson's disease (PD). Although this multidomain protein has been shown to have both GTPase and kinase activities through the Roc and MAPKKK domains, respectively, the protein-protein interactions and pathways involved in LRRK2-mediated signaling remain elusive. Utilizing a combination of protein pull-down assays, mass spectrometry, Western blotting, and immunofluorescence microscopy, this study identifies and describes the interaction between LRRK2 and microtubules. The Roc or GTPase-like domain of LRRK2 is sufficient for interaction with alpha/beta-tubulin heterodimers. This interaction occurs in a guanine nucleotide-independent manner, suggesting that tubulin might not be an effector of the LRRK2 GTPase domain. The R1441C pathogenic mutation, located within the Roc domain, retains interaction with alpha/beta-tubulin heterodimers, suggesting that disruption of this interaction likely is not the mechanism whereby the R1441C mutation leads to disease. At a subcellular level, endogenous LRRK2 protein was found to colocalize with alpha/beta-tubulin in primary hippocampal neurons. These findings are significant in that they link LRRK2 with microtubules, a structural component of the cell that is critically involved in the pathogenesis of several neurodegenerative diseases, including PD.
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PMID:The Roc domain of leucine-rich repeat kinase 2 is sufficient for interaction with microtubules. 1821 93

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of Parkinson's disease (PD). LRRK2 contains a Ras of complex proteins (ROC) domain that may act as a GTPase to regulate its protein kinase activity. The structure of ROC and the mechanism(s) by which it regulates kinase activity are not known. Here, we report the crystal structure of the LRRK2 ROC domain in complex with GDP-Mg(2+) at 2.0-A resolution. The structure displays a dimeric fold generated by extensive domain-swapping, resulting in a pair of active sites constructed with essential functional groups contributed from both monomers. Two PD-associated pathogenic residues, R1441 and I1371, are located at the interface of two monomers and provide exquisite interactions to stabilize the ROC dimer. The structure demonstrates that loss of stabilizing forces in the ROC dimer is likely related to decreased GTPase activity resulting from mutations at these sites. Our data suggest that the ROC domain may regulate LRRK2 kinase activity as a dimer, possibly via the C-terminal of ROC (COR) domain as a molecular hinge. The structure of the LRRK2 ROC domain also represents a signature from a previously undescribed class of GTPases from complex proteins and results may provide a unique molecular target for therapeutics in PD.
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PMID:Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase. 1823 Jul 35

Parkinson's disease (PD) is characterized by progressive dopaminergic neuronal loss in the substantia nigra. The recent discovery of leucine-rich-repeat kinase 2 gene (LRRK2) mutations in PD is significant because these mutations are the most common cause of autosomal dominant PD. Furthermore, a common recurrent mutation (G2019S) is associated with a significant proportion of nonfamilial PD, and a polymorphic variant (G2385R) has been found to increase the risk in the Asian race. The large LRRK2 protein of 280 kD contains three protein-protein interaction domains and two enzymatic domains, the Ras-related GTPase and the kinase. Mutations in these domains have been described in PD patients. Preliminary evidence suggests that some types of LRRK2 mutations increase the kinase activity, and this is associated with significantly higher apoptotic cell death in dopaminergic cell lines and primary neurons; abolishing the kinase function ameliorates this cellular toxicity. It also appears that its GTPase domain can be activated independently, whereas the kinase activity strictly requires the GTPase activation. Mutations in the LRRK2 have displayed notable pleomorphic pathologies that might indicate an upstream role of LRRK2 in cellular signaling pathways. The identification of physiological substrates (likely to be involved in signaling and apoptotic pathways) of LRRK2 remains an important step in our understanding of the role of LRRK2 in the disease process. Further in vitro and in vivo studies will unravel the role of LRRK2 in cell signaling and its impact on proliferation, differentiation, and survival of neurons.
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PMID:Molecular biology changes associated with LRRK2 mutations in Parkinson's disease. 1833 1

In this review, we discuss the evolutionary, biochemical, and functional data available for members of the Roco protein family. They are characterized by having a conserved supradomain that contains a Ras-like GTPase domain, called Roc, and a characteristic COR (C-terminal of Roc) domain. A kinase domain and diverse regulatory and protein-protein interaction domains are also often found in Roco proteins. First detected in the slime mold Dictyostelium discoideum, they have a broad phylogenetic range, being present in both prokaryotes and eukaryotes. The functions of these proteins are diverse. The best understood are Dictyostelium Rocos, which are involved in cell division, chemotaxis, and development. However, this family has received extensive attention because mutations in one of the human Roco genes (LRRK2) cause familial Parkinson disease. Other human Rocos are involved in epilepsy and cancer. Biochemical data suggest that Roc domains are capable of activating kinase domains intramolecularly. Interestingly, some of the dominant, disease-causing mutations in both the GTPase and kinase domains of LRRK2 increase kinase activity. Thus, Roco proteins may act as stand-alone transduction units, performing roles that were thought so far to require multiple proteins, as occur in the Ras transduction pathway.
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PMID:The Roco protein family: a functional perspective. 1852 61

Aggregation of alpha-synuclein may contribute to neuropathology in Parkinson's disease patients and in transgenic animal models. Natively unfolded alpha-synuclein binds to various proteins and conformational changes due to alpha-synuclein misfolding may alter physiological interactions. In the present study, we used protein arrays spotted with 5000 recombinant human proteins for a large scale interaction analysis of monomeric versus oligomeric alpha-synuclein. Monomeric alpha-synuclein bound to arrayed cAMP regulated phosphoprotein 19 and binding appears to be disrupted by alpha-synuclein oligomerization. Incubation with recombinant alpha-synuclein oligomers lead to the identification of several GTPase activating proteins and Cdc42 effector proteins as binding partners. Protein database searches revealed a Cdc42/Rac interactive binding domain in some interactors. To demonstrate in vivo relevance, we analyzed brainstem protein extracts from alpha-synuclein(A30P) transgenic mice. Pull-down assays using beads conjugated with a Cdc42/Rac interactive binding domain lead to an enrichment of endogenous alpha-synuclein oligomers. Cdc42 effector proteins were also co-immunoprecipitated with alpha-synuclein from brainstem lysates and were colocalized with alpha-synuclein aggregates in brain sections by double immunostaining. By two-dimensional gel electrophoretic analysis of synaptosomal fractions from transgenic mouse brains we detected additional isoforms of septin 6, a downstream target of Cdc42 effector proteins. Small GTPases have recently been identified in a genetic modifier screen to suppress alpha-synuclein toxicity in yeast. Our data indicate that components of small GTPase signal transduction pathways may be directly targeted by alpha-synuclein oligomers which potentially leads to signaling deficits and neurodegeneration.
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PMID:Protein array analysis of oligomerization-induced changes in alpha-synuclein protein-protein interactions points to an interference with Cdc42 effector proteins. 1854 83

Small guanosine triphosphatases (GTPases) have long been known to control the activities of downstream protein kinases. Some members of a rather new multidomain protein family contain not only a GTPase domain of the ROC (Ras of complex protein) subtype but also a protein kinase domain, and both domains seem to cooperate with each other in the same polypeptide. Data now show that the kinase activity of one of these ROCO proteins depends on whether guanosine diphosphate or guanosine triphosphate (GTP) is bound and that the activity is controlled by the adjacent GTPase, which suggests a novel mechanism of intrinsic control. This ROCO family member, leucine-rich repeat kinase 2 (LRRK2), is of special interest because mutations within both its protein kinase and its GTPase domains are associated with Parkinson's disease (PD). These mutations lead to abnormally enhanced protein kinase activity, which is believed to cause or at least contribute to neuronal damage. The crystal structure of the GTPase domain of LRRK2 has now been resolved and shows that the ROC GTPase domain is responsible for LRRK2 homodimerization in a surprising way. The structure not only offers insights into the molecular effects of some of the PD-associated mutations of LRRK2, but may also help to improve our understanding of the intrinsic control mechanism between a GTPase and a protein kinase within the same protein.
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PMID:ROCO kinase activity is controlled by internal GTPase function. 1854 47


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