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

Parkinson's disease (PD) is a good target for gene therapy because the lesion is localized to the substantia nigra (SN). There are several approaches in gene therapy for PD. For enhancing dopamine production, the candidate genes are tyrosine hydroxylase, AADC and/or GTP cyclohydroxylase I. The second approach is a neuroprotective strategy, which is based on the usage of genes for neurotophic factors or anti-apoptotic agents. We also showed that Apaf-1-dominant negative inhibitor delivery using an AAV vector system could prevent nigrostriatal degeneration in MPTP mice, suggesting that it might be an anti-mitochondrial apoptotic gene therapy for PD. In 2003, the first gene therapy trial for PD performed at New York Weill Cornell Medical Center. The treatment is designed to deliver glutamic acid decarboxylase (GAD), the gene responsible for making GABA, into the subthalamic nucleus to "quiet down" that nucleus and alleviate Parkinson's symptoms. The last approach is replacement of disease for autosomal recessive PD. Because autosomal recessive juvenile parkinsonism (ARJP) involves the loss of function of parkin gene, gene therapy employing the parkin gene may prevent nigral cell death.
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PMID:[Future of gene therapy for Parkinson's disease]. 1565 40

Parkinson's disease is due to the selective loss of nigrostriatal dopaminergic neurons. Consequently, many therapeutic strategies have focused on restoring striatal dopamine levels, including direct gene transfer to striatal cells, using viral vectors that express specific dopamine biosynthetic enzymes. The central hypothesis of this study is that coexpression of four dopamine biosynthetic and transporter genes in striatal neurons can support the efficient production and regulated, vesicular release of dopamine: tyrosine hydroxylase (TH) converts tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), GTP cyclohydrolase I (GTP CH I) is the rate-limiting enzyme in the biosynthesis of the cofactor for TH, aromatic amino acid decarboxylase (AADC) converts L-DOPA to dopamine, and a vesicular monoamine transporter (VMAT-2) transports dopamine into synaptic vesicles, thereby supporting regulated, vesicular release of dopamine and relieving feedback inhibition of TH by dopamine. Helper virus-free herpes simplex virus type 1 vectors that coexpress the three dopamine biosynthetic enzymes (TH, GTP CH I, and AADC; 3-gene-vector) or these three dopamine biosynthetic enzymes and the vesicular monoamine transporter (TH, GTP CH I, AADC, and VMAT-2; 4-gene-vector) were compared. Both vectors supported production of dopamine in cultured fibroblasts. These vectors were microinjected into the striatum of 6-hydroxydopamine-lesioned rats. These vectors carry a modified neurofilament gene promoter, and gamma-aminobutyric acid (GABA)-ergic neuron-specific gene expression was maintained for 14 months after gene transfer. The 4-gene-vector supported higher levels of correction of apomorphine-induced rotational behavior than did the 3-gene-vector, and this correction was maintained for 6 months. Proximal to the injection sites, the 4-gene-vector, but not the 3-gene-vector, supported extracellular levels of dopamine and dihydroxyphenylacetic acid (DOPAC) that were similar to those observed in normal rats, and only the 4-gene-vector supported significant K(+)-dependent release of dopamine.
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PMID:Coexpression of tyrosine hydroxylase, GTP cyclohydrolase I, aromatic amino acid decarboxylase, and vesicular monoamine transporter 2 from a helper virus-free herpes simplex virus type 1 vector supports high-level, long-term biochemical and behavioral correction of a rat model of Parkinson's disease. 1568 95

Glial cytoplasmic inclusions (GCIs) are characteristic protein deposits in multiple system atrophy (MSA), which are composed of abnormally phosphorylated, partially insoluble alpha-synuclein. In addition, recent studies have shown abnormal widespread accumulation of alpha-synuclein in neurons and neuronal processes, and in several regions including the thalamus and cerebral cortex in MSA. Combined alpha-synuclein and rab3a immunoprecipitation assays have shown alpha-synuclein/rab3a binding in the cerebellum and pons (in which GCIs were present) and in the cerebral cortex (area 8) (in which GCIs were absent) in MSA cases, but not in the cerebellum and cerebral cortex in age-matched controls. Similar findings were found in MSA-C and MSA-P cases (olivopontocerebellar atrophy and striatonigral degeneration types, respectively), thus indicating possible abnormal interactions of alpha-synuclein and rab3a in diseased brains. Abnormal alpha-synuclein binding to rab3a was also found in the substantia nigra but not in the cerebral cortex in Parkinson's disease. These findings suggest membrane and synaptic vesicle trafficking as vulnerable targets in MSA. Since rab3a is a member of the Ras super-family of small (21-25 kDa) GTP-binding proteins which is involved in the regulation of the internal trafficking, exocytosis and neurotransmission, and vesicle endocytosis, the present findings might suggest membrane and synaptic vesicle trafficking as vulnerable targets in MSA.
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PMID:Alpha-synuclein binding to rab3a in multiple system atrophy. 1585 72

Human leucine-rich repeat kinase 1 (LRRK1) is a multi-domain protein of unknown function belonging to the ROCO family of complex proteins. Here, we report the molecular characterization of human LRRK1 and show, for the first time, that LRRK1 is both a functional protein kinase and a GDP/GTP-binding protein. Binding of GTP to LRRK1 is specific, requires the GTPase-like Roc domain, and leads to a stimulation of LRRK1 kinase activity. LRRK1 is the first example of a GTP-regulated protein kinase harboring both the kinase effector domain and the GTP-binding regulatory domain. Hence, we propose a model in which LRRK1 cycles between a GTP-bound active and a GDP-bound inactive state. Moreover, we mutated LRRK1 to mimic mutations previously identified in LRRK2/dardarin, the only human paralogue of LRRK1, that have been linked to autosomal-dominant parkinsonism. We demonstrate that three of four mutations analyzed significantly downregulate LRRK1 kinase activity. Ultimately, the results presented for LRRK1 may contribute to the elucidation of LRRK2's role in the pathogenesis of Parkinson's disease.
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PMID:LRRK1 protein kinase activity is stimulated upon binding of GTP to its Roc domain. 1624 88

In the past decades, there have been numerous studies in the gene therapy for Parkinson's disease (PD), especially in delivering genes of enzymes for dopamine (DA) synthesis. Gene therapy in PD appears to be at the brink of the clinical study phase. However, there are many questions that need to be solved before this approach can be contemplated clinically, especially the question about the control of DA production because too much DA could cause toxicity. Until recently, few studies have investigated the relation between DA production and PD improvement and respective expressed human tyrosine hydroxylase (hTH), human GTP-cyclohydrolase 1 (hGCH1), and human aromatic acid decarboxylase (hAADC) in ex vivo gene therapy for PD. Now, we have developed a simple, fast, and reliable method to assay the activities of TH and AADC and have provided the possibility of ex vivo gene therapy for PD by genetically modifying cells with separate hTH, hGCH1, and hAADC genes. Using the method, we found though hTH, hGCH1, and hAADC genes were expressed, respectively, they could fulfil the function of DA synthesis by incubating together in vitro, and more DA was synthesized in vitro when hTH, hGCH1, and hAADC genes were expressed together rather than hTH and hAADC genes expressed or hTH expressed. The result suggests that we could easily control DA production in ex vivo gene therapy before transplantation. By combining this method and microdialysis, we also could further investigate the DA production in vitro and in vivo and then decide the optimal number and ratio of different transduced cells to improve the therapy of PD. Thus, the method has potential use in ex vivo gene therapy of PD.
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PMID:The assays of activities and function of TH, AADC, and GCH1 and their potential use in ex vivo gene therapy of PD. 1633 39

Mutations in the the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant Parkinson disease and some cases of sporadic Parkinson disease. Here we found that LRRK2 kinase activity was regulated by GTP via the intrinsic GTPase Roc domain, and alterations of LRRK2 protein that reduced kinase activity of mutant LRRK2 correspondingly reduced neuronal toxicity. These data elucidate the pathogenesis of LRRK2-linked Parkinson disease, potentially illuminate mechanisms of sporadic Parkinson disease and suggest therapeutic targets.
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PMID:Kinase activity of mutant LRRK2 mediates neuronal toxicity. 1698 Sep 62

Type 2 transglutaminase (TG2) is a calcium-dependent acyltransferase which also undergoes a GTP-binding/GTPase cycle even though it lacks any obvious sequence similarity with canonical GTP-binding (G) proteins. As an enzyme which is responsible for the majority of transglutaminase (TG) activity in the brain, TG2 is likely to play a modulatory role in nervous system development and has regulatory effect on neuronal cell death as well. Most importantly, numerous studies have presented data demonstrating that dysregulation of TG2 may contribute to the pathogenesis of many neurodegenerative disorders, including Huntington's disease, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis as well as nervous system injuries. Although TG2's involvement in these disease conditions is strongly suggested by various findings, such as the increase of TG2 mRNA expression, protein level and TG activity in the pathological process of these neurodegenerative disorders, as well as the therapeutic effect of TG2 genetic deletion in animal models of Huntington's disease, the precise mechanism underlying TG2's role remain unclear. TG2 was originally proposed to contribute to the pathogenesis of these diseases by facilitating the formation of insoluble protein aggregates, however recent findings clearly indicate that this is likely not the case. Nonetheless, there is data to suggest that TG2 may play a role in neurodegenerative processes by stabilizing toxic oligomers of the disease-relevant proteins, although further studies are needed to validate these initial in vitro findings.
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PMID:Transglutaminase 2 in neurodegenerative disorders. 1712 46

Leucine-rich repeat kinase 2 (LRRK2), a product of a causative gene for the autosomal-dominant form of familial Parkinson's disease (PARK8), harbors a Ras-like small GTP binding protein-like (ROC) domain besides the kinase domain, although the relationship between these two functional domains remains elusive. Here we show by thin-layer chromatographic analysis that LRRK2 stably binds GTP but lacks a GTPase activity in HEK293 and Neuro-2a cells. A ROC domain mutation that converts LRRK2 to a guanine nucleotide-free form (T1348N) abolishes the kinase activity of LRRK2 as well as its phosphate incorporation upon metabolic labeling. The phosphorylation of LRRK2 was inhibited by potential inhibitors for cyclic AMP-dependent protein kinase. These data suggest that binding of GTP to the ROC domain regulates the kinase activity of LRRK2 as well as its phosphorylation by other kinase(s).
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PMID:GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease. 1726 Sep 67

The PARK3 locus on chromosome 2p13 has shown linkage to both the development and age of onset of Parkinson's disease (PD). One candidate gene at this locus is sepiapterin reductase (SPR). Sepiapterin reductase catalyzes the final step in the biosynthetic pathway of tetrahydrobiopterin (BH(4)), an essential cofactor for aromatic amino acid hydrolases including tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. The expression of SPR was assayed using semiquantitative real-time RT-PCR in human post-mortem cerebellar tissue from neuropathologically confirmed PD cases and neurologically normal controls. The expression of other enzymes involved in BH(4) biosynthesis, including aldose reductase (AKR1B1), carbonyl reductase (CBR1 and CBR3), GTP-cyclohydrolase I (GCH1), and 6-pyruvoyltetrahydrobiopterin (PTS), was also examined. Single-nucleotide polymorphisms around the SPR gene that have been previously reported to show association to PD affection and onset age were genotyped in these samples. Expression of SPR showed a significant 4-fold increase in PD cases relative to controls, while the expression of AKR1B1 and PTS was significantly decreased in PD cases. No difference in expression was detected for CBR1, CBR3, and GCH1. Genetic variants did not show a significant effect on SPR expression, however, this is likely due to the low frequency of rare genotypes in the sample. While the association of SPR to PD is not strong enough to support that this is the PARK3 gene, this study further implicates a role for SPR in idiopathic PD.
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PMID:Sepiapterin reductase expression is increased in Parkinson's disease brain tissue. 1727 Jan 57

Mutations in Leucine Rich Repeat Kinase 2 (LRRK2) are the leading genetic cause of Parkinson's disease (PD). LRRK2 is predicted to contain kinase and GTPase enzymatic domains, with recent evidence suggesting that the kinase activity of LRRK2 is central to the pathogenic process associated with this protein. The GTPase domain of LRRK2 plays an important role in the regulation of kinase activity. To investigate how the GTPase domain might be related to disease, we examined the GTP binding and hydrolysis properties of wild type and a mutant form of LRRK2. We show that LRRK2 immunoprecipitated from cells has a detectable GTPase activity that is disrupted by a familial mutation associated with PD located within the GTPase domain, R1441C.
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PMID:The R1441C mutation of LRRK2 disrupts GTP hydrolysis. 1744 67


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