- Email: [email protected]
Consensus on future directions in Parkinson's disease research
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Parkinson's disease research In response to a request by the US Congress, the National Institute of Neurological Disorders and Stroke recently convened a workshop* with the aim of encouraging an exchange of new ideas and defining an agenda for future research on Parkinson's disease. Recurring themes included the recognition that Parkinson's disease probably has a genetic and environmental component; the possibility that many divergent therapeutic strategies will need to be pursued; and the growing belief that neurodegenerative disorders share useful common features. According to Caroline M. Tanner (The Parkinson's Institute, Sunnyvale, CA, USA), 'You might have an abnormality of either more than one detoxifying enzyme, or of a detoxifying enzyme in the liver, as well as another enzyme abnormality in the brain that would minimize your ability to protect against oxidative stress, for example'. The search for the gene or genes involved and their interaction with environmental stimuli in Parkinson's disease has intensified. There is heightened interest, for example, in the role of genetic susceptibility in apparently nonfamilial Parkinson's disease, and the mechanisms of gene penetrance and the possibility of different genetic defects causing the familial versus nonfamilial forms of the disease. Recent efforts to identify environmental neurotoxins have targeted chemicals that block mitochondrial respiration, such as those commonly found in herbicides and pesticides. The latent period between exposure to a potential neurotoxin and the manifestation of disease symptoms may be long in this disease, which will complicate epidemiological studies. It is also a priority to identify biomarkers for Parkinson's disease. These would allow early-stage diagnosis. They would also allow monitoring of both disease progression and the effectiveness of preventive or therapeutic interventions.Genetic and radiological markers [using single-photon emission computer tomography (SPECT) scanning] are all being considered. The latter would be used to detect early evidence of injury to the substantianigra. Other possibilities include the detection of biochemical markers in cerebrospinal fluid or blood, and identificationof early disease-specificclinical signs.
Current theories on the pathogenesis of Parkinson's disease suggest that excitotoxicity, mitochondrial dysfunction, and the formation of free radicals contribute to a neurotoxic oxidative process, as well as the possibilitythat these processes potentiate each other. Renewed interest was also expressed in mitochondrialdysfunctionas a primary cause of free radical formation and, ultimately, neuronal cell death. The possibility was also proposed that Lewy bodies (the neuronal inclusion elements characteristic of Parkinson's disease), and even dopamine itself, might contribute to free radical formation and play a role in cell death as the disease progresses. Marie-Francoise Chesselet (University of Pennsylvania, PA, USA) recommended that clinical trials should evaluate the therapeutic potential of free radical scavengers and drugs that combat excitotoxicity or improve oxidative metabolism: 'there are compelling reasons to think that those processes, even if they are not primary processes, are somehow involved in the cascade that leads to cell death.' She concluded that interrupting this cascade at any point, even in a nonspecific way, could be very beneficial. Dr Chesselet also described a growing interest in trophic factors, particularly glial-cell-derived neurotrophic factor (GDNF), which appears to be able to rescue dopaminergic neurons. Surgical strategies have recentlyshown improved success and reduced risks; they include fetal tissue transplantation, pallidotomy and subthalamic nucleus stimulation.The strategy for transplantation is to establish greater success with fetal cells; at the same time, efforts are underway with gene transfer aimed at engineering non-neuronal cells to produce dopamine or trophic factors. Apart from scientific and clinical considerations, overall reductions in funding for medical research are viewed as the greatest obstacle to future advances in Parkinson's disease. In the USA, the Morris K. Udall Parkinson's Research, Education and Assistance Act is currently under review by the House of Representatives' subcommittee on Health and the Environment; this act would authorize US $100 million in fiscal year 1996 to support basic and clinical research and to establish a Parkinson's Disease Education Program.
*Parkinson's Disease: A Research and Planning Workshop, Washington, DC, 28-30 August 1995.
Vicki Glaser is a science writer based in PA, USA.
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The potentialofneuralstemcells, theearly embryonic precursors of the nervous system, as a source of material for brain transplants has only recently been appreciated. Neural stem cells can also be engineered to carry replacement genes into the nervous system, and the discovery of a residual neural stem cell population m the central nervous systems of adult mammals has opened up longer-term prospects for therapy in humans. According to Professor Fred Gage (Salk Institute, San Diego, CA, USA), the organizer of a recent meeting in Paris*, prospects for these new technologies are 'very encouraging'. Neural stem cells in culture continue to divide to produce a potentially enormous supply of neural precursor cells, which can be increasedeven more by immortalizingthe precursors. Evan Snyder (Harvard Medical School, Boston, MA, USA) finds that immortalized mouse neural precursors transplanted into newborn mice produce neurons that are correctly integrated into structures throughout the brain, but precursors injected into adult rat brains tend to produce mainly glial cells (Anders Bjorkund, Karolinska Institute, Stockholm, Sweden). The nature of the local factors that seem to be crucial for making precursor cells differentiate into either neurons or glia is clearly a key question. The transformation of precursor cells into dopamine-producing neurons by the product of the gene known as sonic hedgehog [Hynes, M. et al. (1995) Neuron 15, 35--44] may be an important step towards using neural precursor cells for brain grafts in patients with Parkinson's disease. Preliminary experiments indicate that engineered immortalized precursors can be used to replace missing proteins in the nervous system. Evan Snyder has successfully corrected a mutant mouse model of a neural lysosomal storage disease (mucopolysaccharidosis VII) and can promote myelin formation in the demyelinating mouse mutant shiverer. Anders Bjorkund finds that spatial memory in elderly rats is improved by transplanting them with cells producing nerve growth factor. Small numbers of neural stem cells persist in normal adult mammalian brains, and Fred Gage and his colleagues have now stimulated them to differentiate into both neurons and glia in vitro. If ways could be found to trigger differentiation in vivo, perhaps human brains could be persuaded to repair themselves from within. Who knows? Neural stem cells engineered to produce the correct mix of differentiationfactors might just do the trick. *Isolation, Characterization and Utilization of CNS Stem Cells; Fondation IPSEN, Paris, 18 September 1995. JenniferAItman is a consultant and science writer specializing in the neurosciences, and is based in London, UK.
I •
m
m
m
m
mm. .
_
, ...
IL,UII UII U
_
Uallla
l'l~
UII I U L U l U UIIIUULIUII;b 111
Parkinson's disease research In response to a request by the US Congress, the National Institute of Neurological Disorders and Stroke recently convened a workshop* with the aim of encouraging an exchange of new ideas and defining an agenda for future research on Parkinson's disease. Recurring themes included the recognition that Parkinson's disease probably has a genetic and environmental component; the possibility that many divergent therapeutic strategies will need to be pursued; and the growing belief that neurodegenerative disorders share useful common features. According to Caroline M. Tanner (The Parkinson's Institute, Sunnyvale, CA, USA), 'You might have an abnormality of either more than one detoxifying enzyme, or of a detoxifying enzyme in the liver, as well as another enzyme abnormality in the brain that would minimize your ability to protect against oxidative stress, for example'. The search for the gene or genes involved and their interaction with environmental stimuli in Parkinson's disease has intensified. There is heightened interest, for example, in the role of genetic susceptibility in apparently nonfamilial Parkinson's disease, and the mechanisms of gene penetrance and the possibility of different genetic defects causing the familial versus nonfamilial forms of the disease. Recent efforts to identify environmental neurotoxins have targeted chemicals that block mitochondrial respiration, such as those commonly found in herbicides and pesticides. The latent period between exposure to a potential neurotoxin and the manifestation of disease symptoms may be long in this disease, which will complicate epidemiological studies. It is also a priority to identify biomarkers for Parkinson's disease. These would allow early-stage diagnosis. They would also allow monitoring of both disease progression and the effectiveness of preventive or therapeutic interventions.Genetic and radiological markers [using single-photon emission computer tomography (SPECT) scanning] are all being considered. The latter would be used to detect early evidence of injury to the substantianigra. Other possibilities include the detection of biochemical markers in cerebrospinal fluid or blood, and identificationof early disease-specificclinical signs.
Current theories on the pathogenesis of Parkinson's disease suggest that excitotoxicity, mitochondrial dysfunction, and the formation of free radicals contribute to a neurotoxic oxidative process, as well as the possibilitythat these processes potentiate each other. Renewed interest was also expressed in mitochondrialdysfunctionas a primary cause of free radical formation and, ultimately, neuronal cell death. The possibility was also proposed that Lewy bodies (the neuronal inclusion elements characteristic of Parkinson's disease), and even dopamine itself, might contribute to free radical formation and play a role in cell death as the disease progresses. Marie-Francoise Chesselet (University of Pennsylvania, PA, USA) recommended that clinical trials should evaluate the therapeutic potential of free radical scavengers and drugs that combat excitotoxicity or improve oxidative metabolism: 'there are compelling reasons to think that those processes, even if they are not primary processes, are somehow involved in the cascade that leads to cell death.' She concluded that interrupting this cascade at any point, even in a nonspecific way, could be very beneficial. Dr Chesselet also described a growing interest in trophic factors, particularly glial-cell-derived neurotrophic factor (GDNF), which appears to be able to rescue dopaminergic neurons. Surgical strategies have recentlyshown improved success and reduced risks; they include fetal tissue transplantation, pallidotomy and subthalamic nucleus stimulation.The strategy for transplantation is to establish greater success with fetal cells; at the same time, efforts are underway with gene transfer aimed at engineering non-neuronal cells to produce dopamine or trophic factors. Apart from scientific and clinical considerations, overall reductions in funding for medical research are viewed as the greatest obstacle to future advances in Parkinson's disease. In the USA, the Morris K. Udall Parkinson's Research, Education and Assistance Act is currently under review by the House of Representatives' subcommittee on Health and the Environment; this act would authorize US $100 million in fiscal year 1996 to support basic and clinical research and to establish a Parkinson's Disease Education Program.
*Parkinson's Disease: A Research and Planning Workshop, Washington, DC, 28-30 August 1995.
Vicki Glaser is a science writer based in PA, USA.
1
350
m
~
temcel
,,
I , ~ l ' ~ l l ~ ~ ' g 0 r: ' ~ ~ 1 - ~: ~ " l m ~ ~ 'll ,,.t;:-I ,5,.~-,.- • ' ~ ' ~l .,~* '~':'~'~" ~'~'~'~'~'l,ltal~l,~,.'mta I~1t,~ .[~'l'l~.'m'141~ , ¢ , l ~ ' 1 4 A r ~ ' l l " ~ ' ~ t t a
~
r,u
o.
i
The potentialofneuralstemcells, theearly embryonic precursors of the nervous system, as a source of material for brain transplants has only recently been appreciated. Neural stem cells can also be engineered to carry replacement genes into the nervous system, and the discovery of a residual neural stem cell population m the central nervous systems of adult mammals has opened up longer-term prospects for therapy in humans. According to Professor Fred Gage (Salk Institute, San Diego, CA, USA), the organizer of a recent meeting in Paris*, prospects for these new technologies are 'very encouraging'. Neural stem cells in culture continue to divide to produce a potentially enormous supply of neural precursor cells, which can be increasedeven more by immortalizingthe precursors. Evan Snyder (Harvard Medical School, Boston, MA, USA) finds that immortalized mouse neural precursors transplanted into newborn mice produce neurons that are correctly integrated into structures throughout the brain, but precursors injected into adult rat brains tend to produce mainly glial cells (Anders Bjorkund, Karolinska Institute, Stockholm, Sweden). The nature of the local factors that seem to be crucial for making precursor cells differentiate into either neurons or glia is clearly a key question. The transformation of precursor cells into dopamine-producing neurons by the product of the gene known as sonic hedgehog [Hynes, M. et al. (1995) Neuron 15, 35--44] may be an important step towards using neural precursor cells for brain grafts in patients with Parkinson's disease. Preliminary experiments indicate that engineered immortalized precursors can be used to replace missing proteins in the nervous system. Evan Snyder has successfully corrected a mutant mouse model of a neural lysosomal storage disease (mucopolysaccharidosis VII) and can promote myelin formation in the demyelinating mouse mutant shiverer. Anders Bjorkund finds that spatial memory in elderly rats is improved by transplanting them with cells producing nerve growth factor. Small numbers of neural stem cells persist in normal adult mammalian brains, and Fred Gage and his colleagues have now stimulated them to differentiate into both neurons and glia in vitro. If ways could be found to trigger differentiation in vivo, perhaps human brains could be persuaded to repair themselves from within. Who knows? Neural stem cells engineered to produce the correct mix of differentiationfactors might just do the trick. *Isolation, Characterization and Utilization of CNS Stem Cells; Fondation IPSEN, Paris, 18 September 1995. JenniferAItman is a consultant and science writer specializing in the neurosciences, and is based in London, UK.