A dynamical-systems model for Parkinson's disease

The juxtaposition of hypokinetic and hyperkinetic symptoms in Parkinson's disease (PD) presents a challenge in modeling the basal ganglia. We propose a model of the striatum that can account for the mixture of symptoms seen in PD. In the model, the problem of motor planning is cast in terms of a particle in a potential, where potentials are generated internally in striatal modules, subject to afferent control. Planned movement is governed by Hamilton's equations, where potential energy is supplied by potentials expressed in the striatum. To test the model in realistic situations, a dynamic simulation of a two-link robot arm was used. Normal movement is modeled and shown to exhibit observed experimental properties. Symptoms of PD are reproduced by modeling hypothetical consequences of PD pathology. Received: 17 February 1999 / Accepted in revised form: 21 December 1999     

Modifications of the iron-neuromelanin system in Parkinson's disease

Parkinson's disease is a common neurodegenerative disorder with a mainly sporadic aetiology, although a number of monogenic familiar forms are known. Most of the motor symptoms are due to selective depletion of dopaminergic, neuromelanin-containing neurones of the substantia nigra pars compacta. Neuromelanin is the dark insoluble macromolecule that confers the black (substantia nigra) or grey (locus coeruleus) colour to monoaminergic basal ganglia. In particular, nigral neurones are pigmented because of the accumulation of by-products of oxidative metabolism of the neurotransmitter dopamine. The occurrence of dopamine (and all the enzymatic machinery required for dopamine synthesis, re-uptake and disposal) and neuromelanin, and a large amount of iron ions that interact with them, makes dopaminergic nigral neurones peculiarly susceptible to oxidative stress conditions that, in turn, may become amplified by the iron-neuromelanin system itself. In this mini-review we describe biophysical evidence for iron-neuromelanin modifications that support this hypothesis. Furthermore, we discuss the formation of the covalent linkage between alpha-synuclein and neuromelanin from the early stages of the disease.     

Gene therapy for Parkinson's disease

Parkinson's disease (PD) is a debilitating neurodegenerative disorder arising from loss of dopaminergic neurons in the substantia nigra pars compacta and subsequent depletion of striatal dopamine levels, which results in distressing motor symptoms. The current standard pharmacological treatment for PD is direct replacement of dopamine by treatment with its precursor, levodopa (L-dopa). However, this does not significantly alter disease progression and might contribute to the ongoing pathology. Several features of PD make this disease one of the most promising targets for clinical gene therapy of any neurological disease. The confinement of the major pathology to a compact, localised neuronal population and the anatomy of the basal ganglia circuitry mean that global gene transfer is not required and there are well-defined sites for gene transfer. The multifactorial aetiology of idiopathic PD means that it is unlikely any single gene will cure the disease, and as a result at least three separate gene-transfer strategies are currently being pursued: transfer of genes for enzymes involved in dopamine production; transfer of genes for growth factors involved in dopaminergic cell survival and regeneration; and transfer of genes to reset neuronal circuitry by switching cellular phenotype. The merits of these strategies are discussed here, along with remaining hurdles that might impede transfer of gene therapy technology to the clinic as a treatment for PD.     

Gene therapy for Parkinson's disease

Gene therapy is a potentially powerful approach to the treatment of neurological diseases. The discovery of neurotrophic factors inhibiting neurodegenerative processes and neurotransmitter-synthesizing enzymes provides the basis for current gene therapy strategies for Parkinson's disease. Genes can be transferred by viral or nonviral vectors. Of the various possible vectors, recombinant retroviruses are the most efficient for genetic modification of cells in vitro that can thereafter be used for transplantation (ex vivo gene therapy approach). Recently, in vivo gene transfer to the brain has been developed using adenovirus vectors. One of the advantages of recombinant adenovirus is that it can transduced both quiescent and actively dividing cells, thereby allowing both direct in vivo gene transfer and ex vivo gene transfer to neural cells. Probably because the brain is partially protected from the immune system, the expression of adenoviral vectors persists for several months with little inflammation. Novel therapeutic tools, such as vectors for gene therapy have to be evaluated in terms of efficacy and safety for future clinical trials. These vectors still need to be improved to allow long-term and possibly regulatable expression of the transgene.     

A neuroprotective role for angiogenin in models of Parkinson's disease

We previously observed marked down-regulation of the mRNA for angiogenin, a potent inducer of neovascularization, in a mouse model of Parkinson's disease (PD) based on over-expression of alpha-synuclein. Angiogenin has also been recently implicated in the pathogenesis of amyotrophic lateral sclerosis. In this study, we confirmed that mouse angiogenin-1 protein is dramatically reduced in this transgenic alpha-synuclein mouse model of PD, and examined the effect of angiogenin in cellular models of PD. We found that endogenous angiogenin is present in two dopamine-producing neuroblastoma cell lines, SH-SY5Y and M17, and that exogenous angiogenin is taken up by these cells and leads to phosphorylation of Akt. Applied angiogenin protects against the cell death induced by the neurotoxins 1-methyl-4-phenylpyridinium and rotenone and reduces the activation of caspase 3. Together our data supports the importance of angiogenin in protecting against dopaminergic neuronal cell death and suggests its potential as a therapy for PD.     

A two-stage meta-analysis identifies several new loci for Parkinson's disease

A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson''s Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson''s disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p<5×10⁻¹⁰, PARK16/1q32, STX1B/16p11, FGF20/8p22, STBD1/4q21, and GPNMB/7p15). Two of these five loci have been suggested by previous association studies (PARK16/1q32, FGF20/8p22), and this study provides further support for these findings. Using a dataset of post-mortem brain samples assayed for gene expression (n = 399) and methylation (n = 292), we identified methylation and expression changes associated with PD risk variants in PARK16/1q32, GPNMB/7p15, and STX1B/16p11 loci, hence suggesting potential molecular mechanisms and candidate genes at these risk loci.     

Targets for neuroprotection in Parkinson's disease

Current therapies for Parkinson's disease significantly improve the quality of life for patients suffering from this neurodegenerative disease, yet none of the current therapies has been convincingly shown to slow or prevent the progression of disease. Much has been learned about the pathophysiology of Parkinson's disease in recent years, and these discoveries offer a variety of potential targets for protective therapy. Mechanisms implicated in the disease process include oxidative stress, mitochondrial dysfunction, protein aggregation and misfolding, inflammation, excitotoxicity, and apoptosis. At the same time, the involvement of these diverse processes makes modeling the disease and evaluation of potential treatments difficult. In addition, available clinical tools are limited in their ability to monitor the progression of the disease. In this review, we summarize the different pathogenic mechanisms implicated in Parkinson's disease and neuroprotective strategies targeting these mechanisms currently under clinical study or under preclinical development, with a view towards strategies that seem most promising.     

Cell replacement therapy for Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder in which the degeneration of dopaminergic neurons projecting from the substantia nigra to the striatum is a key pathological feature of the disease. Although pharmacological dopamine replacement is generally very effective in early disease, it is only a symptomatic therapy and can have significant side effects with long term use. One of the key strategies in a more restorative approach to PD therapy involves replacement of this degenerating nigro-striatal dopaminergic network with cells and several possible cell sources are being explored. While much experience and some success have been gained with fetal ventral mesencephalic (FVM) tissue transplants, the rapidly advancing stem cell field is providing attractive alternative options which circumvent many of the ethical and practical problems inherent in trials with FVM tissue. Of these embryonic stem cells and induced pluripotent stem cells seem the most promising. However further development and optimisation of the safety and efficacy of the techniques involved in generating and manipulating these, as well as other, cell sources will be essential before any further clinical trials are carried out.     

Gene therapy approaches for Parkinson's disease

Proteome analysis is usually performed by separating complex cellular protein extracts by two-dimensional-electrophoresis followed by protein identification using mass spectrometry. In this way proteins are compared from normal and diseased tissue in order to detect disease related protein changes. In a strict sense, however, this procedure cannot be called proteome analysis: the tools of proteomics are used just to detect some interesting proteins which are then investigated by protein chemistry as usual. Real proteome research would be studying the cellular proteome as a whole, its composition, organization and its kind of action. At present however, we have no idea how a proteome works as a whole; we have not even a theory about that. If we would know how the proteome of a cell type is arranged, we probably would alter our strategy to detect and analyze disease-related proteins. I will present a theory of proteomics and show some results from our laboratory which support this theory. The results come from investigations of the mouse brain proteome and include mouse models for neurodegenerative diseases.     

Deep brain stimulation for Parkinson's disease

Deep brain stimulation at high frequency was first used in 1997 to replace thalamotomy in treating the characteristic tremor of Parkinson's disease, and has subsequently been applied to the pallidum and the subthalamic nucleus. The subthalamic nucleus is a key node in the functional control of motor activity in the basal ganglia. Its inhibition suppresses symptoms in animal models of Parkinson's disease, and high frequency chronic stimulation does the same in human patients. Acute and long-term results after deep brain stimulation show a dramatic and stable improvement of a patient's clinical condition, which mimics the effects of levodopa treatment. The mechanism of action may involve a functional disruption of the abnormal neural messages associated with the disease. Long-term changes, neural plasticity and neural protection might be induced in the network. Similar effects of stimulation and lesioning have led to the extension of this technique for other targets and diseases.     

A community survey of Parkinson's disease.

In a rural community of 80,000 people 69 patients were identified as having a diagnosis of Parkinson''s disease. After interview and examination we found that 55 met the generally accepted diagnostic criteria for Parkinson''s disease, 4 had possible Parkinson''s disease, 6 had essential tremor, 2 had dementia and 2 had other conditions. The patients with Parkinson''s disease had clinical and epidemiologic characteristics similar to those of patients in previous, mainly hospital-based, studies. These characteristics included mean age at onset (63 years), frequency rate of dementia (20%) and presence of postural tremor (11%). The pattern of treatment varied, some patients receiving more medication than is usual for the severity of their illness, and some patients receiving less than is usual. Parkinson''s disease can be difficult to diagnose and manage because of the clinical variation between patients in presentation and response to treatment.     

Mitochondria and ubiquitin-proteasomal system interplay: relevance to Parkinson's disease

The cellular mechanisms that may underlie the death of dopaminergic neurons in Parkinson's disease are ubiquitin-proteasomal system (UPS) impairment, mitochondrial dysfunction, and oxidative stress. The goal of this work was to elucidate the correlation between mitochondrial dysfunction and UPS impairment, focusing on the role of oxidative stress. Our data revealed that mitochondria-DNA-depleted cells (rho0) are compromised at the mitochondrial and UPS levels and also show an alteration of the oxidative status. In parental cells (rho+), MPP(+) induced a clear inhibition of complex I activity, as well as an increase in ubiquitinylated protein levels, which was not observed in cells treated with lactacystin. Moreover, MPP(+) induced a decreased in the 20S chymotrypsin-like and peptidyl-glutamyl peptide hydrolytic-like proteolytic activities after 24 h of exposure. ROS production was increased in rho+ cells treated with MPP(+) or lactacystin, at early treatment periods. MPP(+) induced an increase in carbonyl group formation in rho+ cells. The results suggest that a mitochondrial alteration leads to an imbalance in the cellular oxidative status, inducing a proteasomal deregulation, which may exacerbate protein aggregation, and consequently degenerative events.     

Dysfunction of the ubiquitin–proteasome system in Parkinson's disease

Stan Tuček was a neurochemist of international stature whose research encompassed the whole cholinergic field. His collaborations with eminent scientists in Canada, France, the UK and the USA gave him a truly global vision. During the time when contacts between scientists in Eastern Europe and the rest of the world were severely restricted for political reasons, Stan managed to facilitate such contacts, exemplified by the international symposium he organised in 1978 on 'The Cholinergic Synapse' in Western Bohemia, where many established cholinergists from the East and West were able to meet for the first time. He was an enthusiastic member of ESN Council, becoming our President in 1984. In 1986 he hosted a most successful meeting of the ESN in Prague at a time of the utmost political difficulty. It was typical of Stan's dedication and ability to work quietly behind the scenes that international political problems were overcome without fuss. As an acknowledged leader in neuroscience he is sorely missed by his many friends throughout the world.