Decreased tyrosine hydroxylase messenger RNA in the surviving dopamine neurons of the substantia nigra in Parkinson's disease: an in situ hybridization study.
The data suggest that, in PD: (1) TH protein content is decreased in the surviving nigral dopaminergic neurons, most likely as a result of a lowered TH mRNA cellular content.
We investigated TH polymorphism in 44 patients with sporadic PD, 48 patients with familial PD and 89 of their unaffected relatives, and 50 control subjects.
A defective herpes simplex virus type 1 vector expressing human tyrosine hydroxylase was delivered into the partially denervated striatum of 6-hydroxydopamine-lesioned rats, used as a model of Parkinson's disease.
With future improvement in the gene transduction procedure for more efficient, sustained expression of the TH transgene in vivo, genetically engineered DOPA-producing astrocytes hold great promise as a tool to explore the potential of ex vivo gene therapy in Parkinson's disease.
Idiopathic Parkinson's disease (IPD) is characterised by the loss of pigmented neurones in the substantia nigra, leading to reduced tyrosine hydroxylase activity and depletion of dopamine.
We have demonstrated that HSV-1 plasmid vectors which express tyrosine hydroxylase can cause long-term biochemical and behavioral recovery in the 6-hydroxydopamine rat model of Parkinson's disease.
Characterization of intrastriatal recombinant adeno-associated virus-mediated gene transfer of human tyrosine hydroxylase and human GTP-cyclohydrolase I in a rat model of Parkinson's disease.
Thus, a logical and efficient treatment strategy for PD is based on correcting or bypassing the enzyme deficiency by treatment with L-DOPA, DA agonists, inhibitors of DA metabolism, or brain grafts with cells expressing TH.
Data indicate that the adenoviral transduction of the human TH gene to astrocytes and its introduction to the striatum is a promising approach for the treatment of Parkinson's disease.
These results indicate that the GFAP promoter is sufficiently active to enable production of therapeutic levels of dopamine from a GFAP-TH transgene, and suggest the use of astrocytes for gene therapy for Parkinson's disease.
Our results also confirm that future effective gene replacement approaches to Parkinson's disease will have to consider the concomitant transfer of TH and GTP-cyclohydrolase transgenes because the synthesis of the TH cofactor tetrahydrobiopterin may be crucial for restoration of the dopaminergic deficit.
Parkinson's disease is an obvious target for the development of gene therapy procedures which could involve both the delivery of the gene encoding tyrosine hydroxylase to boost dopamine production or the delivery of genes encoding neurotrophic factors such as GDNF to promote the survival of dopaminergic neurons.
A promising approach to the gene therapy of PD is intrastriatal expression of dopamine-synthesizing enzymes [tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC)].
However, non-melanised neurons showed significantly higher TH mRNA (0.163+/-0.006, n=87) than non-melanised neurons in control subjects (P<0.005) and melanised neurons in the PD cases (P<0.0005).
The injection of F(ab')(2) fragments of PD IgG was able to induce TH-positive neuronal loss in the SNpc only when the injected animals raised antibodies against the injected human IgG fragments, which confirmed the importance of the Fcgamma R in microglial activation and nigral injury.
The discrete changes in the levels of dopamine D1 and D3 receptors and tyrosine hydroxylase mRNA in cerebellum from l-DOPA treated Parkinson's disease patients suggests that this brain area has a role in the symptoms of Parkinson's disease and/or the beneficial/side-effects of treatment.
Bovine papilloma virus type-1 (BPV-1)-based expression plasmids TkBPVTH and CGalBPVTH encoding the rat tyrosine hydroxylase (TH) enzyme have been designed for the development of gene therapy for experimental Parkinson's disease.
Brain gene-targeting technology is used to reversibly normalize tyrosine hydroxylase (TH) activity in the striatum of adult rats, using the experimental 6-hydroxydopamine model of Parkinson's disease.
The expression domain of uch-L1 overlaps with that of tyrosine hydroxylase, a molecular marker for dopaminergic neurons, in the ventral diencephalon, an equivalent structure to the substantia nigra where PD progresses in human.
These results may be relevant for the generation of TH/DA-producing human neural cells for in vitro and neurotransplantation research in Parkinson's disease.