ROME—The past decade has seen remarkable progress in understanding the factors that cause Parkinson’s disease. While the field still lacks a “grand unified theory,” significant conceptual advances have been made, and what appears to be a coherent picture may be forming. In the optimistic words of J. William Langston, MD, “I truly believe that finding the cause of Parkinson’s disease is within our reach.” Dr. Langston and three other researchers presented their ideas at the Eighth International Congress of Parkinson’s Disease and Movement Disorders.

CLUES FROM TOXINS AND EPIDEMIOLOGY

“The oldest debate in the field of Parkinson’s disease is whether the disease is environmental or inherited,” said Dr. Langston, pointing out that Charcot held the former position, and Gowers the latter. A major step forward in understanding both potential environmental causes and neuronal pathogenesis was taken with the discovery of parkinsonism in a small group of heroin addicts in the San Francisco Bay area in the mid-1980s. They had taken a form of synthetic heroin contaminated with the toxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and rapidly developed a “remarkably faithful replica of typical Parkinson’s disease,” he said. Dr. Langston, who is Founder and President of the Parkinson’s Institute in Sunnyvale, California, treated the patients and was instrumental in unraveling the mystery of these “frozen addicts.”

The highly selective toxicity of MPTP—it affects the substantia nigra only—led to the rapid development of animal models. Since then, other environmental poisons, including rotenone and paraquat, have been discovered to cause nigral damage. “There is a growing list of dopaminergic toxins out there,” Dr. Langston said. Nonetheless, the known toxins are responsible for only the smallest handful of Parkinson’s disease cases. If environmental toxicity is to blame for most Parkinson’s disease, the culprit has yet to be identified.

Further insights into Parkinson’s disease etiology can be gleaned by looking at epidemiology. The association of cigarette smoking with reduced risk of Parkinson’s disease is “the most robust finding in all of neuroepidemiology,” with over 50 studies conducted. Of these, only six have failed to show a reduced risk, and none show an increased risk. The reduction is dose-dependent and appears to be effective even 20 years before onset of disease. From this data Dr. Langston concluded that “this is probably due to a real biological effect that prevents patients from contracting the disease,” rather than a noncausal association or a reflection of premorbid smoking avoidance in those at risk for Parkinson’s disease.

Based on twin studies—including a recent Swedish Twin Registry—those who develop Parkinson’s disease before age 50 are more likely to have a genetic form of the disease, whereas late forms of the disease are more likely due to environmental etiology. Since less than 4% of Parkinson’s disease cases occur before age 50, he said, “If we’re going to solve Parkinson’s disease, we’ve got to understand these older cases.”

But if there is some ubiquitous environmental toxin, why don’t more people develop the disease? One possible factor, Dr. Langston proposed, lies in the integrity of the blood-brain barrier. He cited a 1994 paper in Cell showing that absence of a single membrane protein in mice caused a dramatic increase in the brain levels of a pesticide that would normally be excluded. Mice with this defect were healthy until they were exposed to pesticide and then rapidly developed a severe neurological disorder. Perhaps, said Dr. Langston, “genes load the gun, and the environment pulls the trigger.”

ALPHA-SYNUCLEIN

The issue of genetic contributions to Parkinson’s disease was taken up by John Hardy, PhD, Chief of the Laboratory of Neurogenetics at the National Institute on Aging. “I think we really do understand a lot about the etiology for many neurodegenerative diseases,” he said. He noted the strong connection between Alzheimer’s disease and chromosome 21 trisomy, and the causative role of excess amyloid precursor protein. Certain tau haplotypes are a proven risk factor for progressive supranuclear palsy and corticobasal ganglionic degeneration.

Similarly, the presence of alpha-synuclein–positive Lewy bodies is clearly associated with Parkinson’s disease, as well as Lewy body dementia. “I regard these diseases as having the same etiology,” Dr. Hardy said. “Just as strokes can hit different parts of the brain, so can Lewy bodies.” Alpha-synuclein was the first protein associated with Parkinson’s disease, when a gene mutation was discovered in two families with autosomal dominant disease.

But frank mutations are not the cause of most Parkinson’s disease cases. “Because we knew that tau haplotypes are predisposed to progressive supranuclear palsy and corticobasal degeneration, we decided to look at alpha-synuclein haplotypes in Parkinson’s disease,” he said. They found that polymorphisms in the promoter region were associated with differences in risk for Parkinson’s disease among patients, and that increased expression of alpha-synuclein was correlated with increased risk.

The role of alpha-synuclein was recently further strengthened by the discovery of several unrelated families with duplications or triplications of the gene. “These families get Parkinson’s disease for a very simple reason,” said Dr. Hardy. “It’s a very simple dosage effect.” As a result, he said, “We don’t say anymore that we don’t know the cause of Parkinson’s disease. One cause is synuclein overexpression.”

MITOCHONDRIAL STRESS

How is Parkinson’s disease set in motion? Two major lines of evidence point to two related, but still competing models. The first stresses the importance of mitochondrial electron transport chain dysfunction, leading to oxidative stress and neuronal death. The second, relatively newer hypothesis focuses on the protein degradation machinery of the ubiquitin-proteasome system. Disruption of this system induces cell death through as-yet-unknown pathways.

The case for the primacy of mitochondrial dysfunction was made by Serge Przedborski, MD, PhD, Professor of Neurology and Pathology at Columbia University in New York City. “MPTP can recapitulate most of the hallmarks of Parkinson’s disease,” he pointed out, and this toxin is a specific inhibitor of mitochondrial complex I. The MPTP metabolite MPP+ (1-methyl-4-phenylpyridine) causes electrons to accumulate instead of being passed to oxygen, leading to the production of a variety of toxic species in the mitochondrion, as well as a deficit of adenosine triphosphate. MPP+ also accumulates in synaptic vesicles, leading to an excessive accumulation of dopamine in the cytosol, which causes a “massive production” of reactive oxygen species. Two of the proteins damaged by this oxidative stress are DJ-1 and parkin. Inactivating mutations in parkin are the most common inherited form of Parkinson’s disease, and damage to parkin by reactive oxygen species inactivates it as well.

This combination of energy crisis and oxidative damage leads to release of cell death triggers from the mitochondria. Once cells start dying, the metabolic burden on the remaining cells is higher, which increases the risk of excitotoxicity in them. Finally, an inflammatory response occurs, which can become self-sustaining long after the original insult. Dr. Przedborski and colleagues recently used copolymer-1 to immunize mice against the inflammatory damage resulting from MPTP exposure.

Dr. Przedborski reiterated that MPTP itself is not the cause of Parkinson’s disease. But the pathogenic cascade it models may offer important insights into how the disease arises and is propagated. “There is a common path for pathogenesis. When you go along this cascade, there are many points of entry,” he said. “Downstream events all converge on the same point”—namely clinical Parkinson’s disease.

PROTEASOMAL DYSFUNCTION

The case for the ubiquitin-proteasome system (UPS) was presented by Kevin St. P. McNaught, PhD, Assistant Professor of Neurology at Mount Sinai School of Medicine in New York City. “We think there is good evidence that the UPS is playing a role in the more common sporadic forms of Parkinson’s disease,” he said.

The UPS is the primary pathway for degrading and clearing proteins that have been damaged or are no longer needed. To enter this pathway, proteins are tagged with ubiquitins and then enter the large multiprotein proteasome complex, where they are broken into peptide fragments. Parkin is a ubiquitin ligase, and loss-of-function mutations cause early-onset Parkinson’s disease. Evidence also shows that alpha-synuclein accumulation can result from inactivation of the UPS, further strengthening the links among the various known causes of Parkinson’s disease.

Studies have shown that Parkinson’s disease patients have significantly reduced levels of a proteasomal subunit in the substantia nigra compared to age-matched healthy controls, and proteasomal function in the nigra is 50% less in Parkinson’s disease patients. Additionally, proteasome activators do not become up-regulated in the face of proteasomal dysfunction in the nigra of patients with Parkinson’s disease, while other brain regions have a more normal compensatory response.

Dr. McNaught also noted that unlike MPTP or rotenone, proteasomal inhibitors are widespread in the environment, being natural products of plants, fungi, and bacteria. To test the ability of proteasome inhibitors to replicate features of Parkinson’s disease, he and his colleagues exposed rats for two weeks to epoxin, an inhibitor produced by Actinomycete fungi, or to the synthetic inhibitor PSI.

In both cases, motor dysfunction began one to two weeks after the last injection and was characterized by slowed movements, tremor, and rigidity that could be reversed by apomorphine. Over the same time period, proteasomal function in the ventral midbrain and lower brain stem was reduced by 40%, while it remained above normal elsewhere in the brain. Neuroimaging at four months indicated a 40% reduction in striatal dopamine transporter binding. Intracytoplasmic inclusions were found in the nigra, locus coeruleus, and dorsal motor nucleus, which stained positive for ubiquitin, parkin, and alpha-synuclein, similar to human Lewy bodies. Microglia infiltrated the affected areas. Anthony Lang, MD, Director of the Movement Disorders Center at Toronto Western Hospital, called the results from this new model “fascinating,” especially since the distribution of the neuropathology seemed to accord well with the human disease.

“These results raise the possibility that exposure to these compounds is responsible for some forms of Parkinson’s disease,” Dr. McNaught concluded. He noted that naturally occurring inhibitors are found in rural areas and in well water, both of which are associated with increased risk for Parkinson’s disease. Regarding the connections to other pathogenic factors, he said, “We should bear in mind that all these systems are interlinked, including the UPS and the mitochondria. Oxidative stress induces proteasome dysfunction and suppresses proteasome up-regulation.”

PUZZLE PIECES

Summing up, Dr. Langston said, “I think we’re seeing more and more pieces of this puzzle. Our job is to put all these together.”

Dr. Hardy, however, was not yet ready for a grand unified theory. “I’m not sure we have just one jigsaw puzzle,” he remarked, “or whether we have two or three scattered on the floor.”

NR

—Richard Robinson

Suggested Reading
Farrer M, Maraganore DM, Lockhart P, et al. alpha-Synuclein gene haplotypes are associated with Parkinson’s disease. Hum Mol Genet. 2001;10:1847-1851.
McNaught KS, Perl DP, Brownell AL, Olanow CW. Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson’s disease. Ann Neurol. 2004; 56:149-162.
Wirdefeldt K, Gatz M, Schalling M, Pedersen NL. No evidence for heritability of Parkinson disease in Swedish twins. Neurology. 2004;63:305-311.

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