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Solving The Parkinsonís Puzzle
Dr. Stanley Fahn Reports
In his Presidential Lecture at the American Academy of Neurology's 55th Annual Meeting in Honolulu, Stanley Fahn, MD, Scientific Director of PDF, presented an overview of some new developments in the understanding of Parkinson's disease. Dr. Fahn is Director of the Center for Parkinson's Disease and Other Movement Disorders at Columbia University, and is one of the most respected leaders in the world in the field of Parkinson's disease. What follows are some edited excerpts from his address.
The Roles of Genes and Environment
The picture that is emerging indicates that PD develops when genetic susceptibility combines with environmental triggers. The dopamine-containing neurons in the substantia nigra are normally under stress from the process of oxidation. When these neurons are then exposed to additional levels of oxidative stress, or to an accumulation of toxic proteins, these nerve cells become unable to cope. This stress in turn causes reactions in the brain tissue surrounding the cells, including the creation of inflammatory glial cells, that can lead to additional problems. The neurons first become dysfunctional and then start to die.
The Importance of 'Parkin'
The gene for the protein called parkin has generated a great deal of excitement in recent years. The parkin gene was first implicated in very rare cases of juvenile PD, in which symptoms begin as early as childhood. In this age group, both copies of the abnormal gene are present, one from the patient's father and one from the mother. This type of inheritance pattern is called "autosomal recessive."
More recently, geneticists have reported that mutations (abnormal changes) in the parkin gene have now been found also in people with typical adult-onset PD (though this still represents only a small fraction of all PD patients). A study published in 2003 described 35 patients with PD who had parkin mutations and whose symptoms became apparent later than age 60. Thirty of these patients had only one, rather than two, defective gene copies. This genetic condition is called heterozygosity. This finding may indicate that the likelihood of developing PD increases with decreasing function of parkin - that is, the more powerful combination of two defective genes would lead to early onset, while with one only, onset would be later.
Probably more cases are gene-related than we had previously appreciated. Parkin and the other autosomal recessive gene mutations need to be closely evaluated in the sporadic adult-onset PD population. It may be that heterozygous mutations of these recessive genes could account for many adult-onset sporadic cases of PD.
What does this mean for people who have PD? Further study will be needed to assess what proportion of people with typical late-onset PD carry a single parkin mutation, and it is too soon to tell how much the risk of PD is increased by a single mutation. In any event, it is likely that the mutation only leads to PD in a person who is also exposed to additional risk factors from other sources. The great majority of cases are of unknown cause and are suspected to be due to a combination of both genetic and environmental factors.
Parkin's normal function also provides a clue to the molecular events underlying cell death in the substantia nigra, the part of the brain that degenerates in PD. Proteins in all cells must "fold" into the right shape in order to function properly, and misfolded proteins can cause trouble. The parkin protein normally helps the cell dispose of specific misfolded and altered proteins. A growing body of evidence indicates that defects in the protein "disposal system," known as the proteasome, may be an important central step in the development of PD.
Alpha-synuclein, Toxic Protofibrils and Lewy Bodies
Another important protein in PD is alpha-synuclein. If there is an excess of alpha-synuclein or if it is abnormal (that is, with a genetic mutation), alpha-synuclein cannot be normally disposed and recycled. Instead, it accumulates and its structure is altered to insoluble forms, known as "protofibrils." New research indicates these protofibrils may be toxic to the cell. The cell tries to protect itself against the toxic protofibrils by combining them into insoluble fibrils that are stored in substances known as Lewy bodies. (Lewy bodies are the characteristic microscopic pathologic hallmark of PD.) In this manner, Lewy bodies serve as protective devices, storing the alpha-synuclein fibrils and thereby removing the toxic protofibrils.
There is a relationship between alpha-synuclein and dopamine. Dopamine is a neurotransmitter - that is, a chemical released by one neuron to stimulate another. Neruons in the substantia nigra produce large amounts of dopamine, which are stored in the nerve terminals before being released to do their work as neurotransmitters. Some molecules of dopamine are oxidized before being stored, and the oxidized product is called dopamine quinone. This quinone can combine with alpha-synuclein, which results in an increase of protofibril formation, instead of the alpha-synuclein being disposed in the normal fashion. If this model is correct, it helps explain why substantia nigra neurons are so vulnerable: They are the main producers of dopamine in the brain. This model in turn helps explains the selective potential toxicity of alpha-synuclein.
Inflammation: Making a Bad Situation Worse
Inflammation, which is the body's response to tissue damage, is known to occur in the brain of patients with PD. Inflammatory changes are not the main culprits behind PD, but they but may aggravate its pathogenesis - this is, the way the disease develops. This means in turn that anti-inflammatory drugs may have potential as treatments. A new study in animals at Columbia University in part funded by the Parkinson's Disease Foundation, indicates that an inflammation-enhancing enzyme, called COX-2, can also enhance production of dopamine quinone. This suggest that drugs which inhibit COX-2 activity would be worthwhile to test in a clinical trial in patients with PD.
Several pathogenetic mechanisms appear to be playing a role in the development of PD. These include oxidative stress, abnormal proteins, impaired protein disposal, inflammatory changes, and mitochondria alterations, and they are interrelated. Attempts to slow the progress of PD will likely be more successful if multiple pathogenetic targets can be attacked simultaneously.
Neuroprotection: Finding Ways to Slow the Progression of Parkinson's
It is too soon to know if antioxidants, anti-inflammatory drugs, COX-2 inhibitors, or any other agent, will actually help slow the development of PD. Clinical trials testing potential agents are needed. Selegiline, commonly used for PD symptoms, was one of the first drugs tested for its potential to slow PD progression. Selegiline was shown to offer a mild symptomatic benefit and to delay the need for levodopa. When selegiline was compared against a placebo in patients who were already taking levodopa, it continued to slow the worsening of parkinsonian symptoms. This suggests that selegiline may have some neuroprotective effect.
Another agent that has already been in preliminary trials is coenzyme Q10, a substance that is present in mitochondria. Very high doses were found to be well tolerated and to slow the rate of clinical worsening, but because this was just a small trial, a much larger one will be needed to prove it has neuroprotective effects.
Other agents currently being examined to see if they can help slow down disease progression include drugs that inhibit cell death, called anti-apoptotic drugs. Patients with PD are needed to participate in controlled clinical trials. The PDF is supporting the Parkinson Study Group, which is conducting many of these trials. Their website is www.parkinson-study-group.org. The National Institutes of Health also sponsors neuroprotective trials; their website is www.ninds.nih.gov.