Researchers made progress in 2006 along the long road from basic research to new treatments for diseases related to human movement. Laboratory studies of protein folding, inflammation, growth factors, and genetics have suggested new ways to monitor and treat these disorders. Some treatments are now being tested in animals and humans.
Protein Misfolding: Friends or Enemies?
A protein’s shape determines what it does in the body. Cells make proteins composed of long strings of subunits called amino acids, which coil and fold to form three-dimensional shapes. Incorrectly folded proteins do not interact properly with other proteins. Misfolded proteins may also attach to each other and form clumps called inclusions, which are common in the brains of people with some neurological disorders.
Alpha-synuclein is a major component of the inclusions (called Lewy bodies) typically found in brain cells of people with Parkinson’s disease, a disorder that causes rigidity, tremors, and slow movement. Lewy bodies are also found in a related form of dementia called, appropriately, dementia with Lewy bodies. Alpha-synuclein-rich inclusions are also found in multiple system atrophy, which may resemble Parkinson’s disease and cause problems with speech, balance, and coordination.
Two recent studies, by Thomas Südhof and colleagues (reported in Cell) and by Tracey Dickson and colleagues (reported in Experimental Neurology), suggest that the normal function of alpha-synuclein is to protect nerve cells from damage.1,2 Normal levels of properly folded alpha-synuclein, then, seem to protect cells, but overproduction, misfolding, and aggregation of the protein are associated with disease. How?
Although there is some controversy on the issue, it is generally believed that protein misfolding and aggregation contribute to cell death, but the process remains unclear. It may be that the misfolded proteins are unable to do their normal jobs, but they also appear to interfere with the cell’s other functions. A study led by Richard Morimoto, reported in Science, suggests that an excess of misfolded proteins can overwhelm the cell’s “quality control” system, resulting in misfolding of other proteins.3 Another study, by Susan Lindquist and colleagues and published in Science, suggests that excess alpha-synuclein interferes with the movement of proteins within cells.4
Based on the hypothesis that inclusions contribute to cell damage, some therapies are being developed to prevent aggregation and inclusions. In contrast, a team led by David Housman and Aleksey Kazantsev tried the opposite approach, according to their report in Proceedings of the National Academy of Sciences.5 They suspected that aggregation of misfolded proteins might be the cell’s way of protecting itself from the damaging effects of misfolded protein and that inclusions might protect cells instead of damaging them. When they tested a drug they called B2, which promotes inclusion formation, they found that it actually reduced cell damage in cellular models for Huntington’s disease and Parkinson’s disease.
In a commentary appearing in Experimental Neurology, Mark Cookson offered an explanation for the apparent paradoxical effects of alpha-synuclein.6 He proposed that normal, modest levels of alpha-synuclein protect nerve cells. As the cell is stressed, it makes more alpha-synuclein in an attempt to protect itself from damage. Alpha-synuclein begins to form small aggregates, which interfere with normal cellular function. If the smaller aggregates can be clumped together into inclusions, they are prevented from damaging the cell. A better understanding of the role of misfolded proteins in neurodegenerative disease will help guide development of new drugs to prevent that damage.
A cell’s defense?: A stressed cell, center, makes more alpha-synuclein, a protein in the brain, possibly to protect itself from the damaging effects of misfolded proteins in neurodegenerative diseases such as Parkinson’s. (Image courtesy of Mark Cookson)
Inflammation and Parkinson’s Disease
In Parkinson’s disease, a specific population of nerve cells dies prematurely. The question is why. One possibility is that inflammation, a clustering of reactive cells, may play a role. James Bower and his fellow researchers at the Mayo Clinic College of Medicine compared the medical records of 196 patients with Parkinson’s disease to 196 matched controls. In the study, published in Neurology, they found that patients who went on to develop Parkinson’s disease were more likely to have asthma, allergic rhinitis, or hay fever than controls.7
These findings suggest that some people may have immune responses that contribute to both allergies and Parkinson’s disease. Along these same lines, Bower’s group also found that drugs that block inflammation, such as nonsteroidal anti-inflammatory drugs (NSAIDs), may have protective effects—that is, those who take NSAIDs may be less likely to get Parkinson’s disease.
Together, this research helps link inflammation with Parkinson’s disease, although more study is needed to determine how the two are related. Understanding the nature of this link may provide important new insights into the disease process and suggest new treatment strategies.
A group led by Miguel Hernán published a similar study in Neurology.8 They found that men who used non-aspirin NSAIDs (such as ibuprofen) were 20 percent less likely to develop Parkinson’s disease, while women who used NSAIDs were 20 percent more likely to develop Parkinson’s disease than people who did not use these drugs. The sex difference was unexpected and supports the findings of some other studies in which the risk factors for Parkinson’s disease were different for men than for women.
Another study has shown that an antibiotic used to treat acne since the 1970s inhibits inflammation and protects neurons. Raymond Swanson and colleagues at the University of California and Veterans Affairs Medical Center in San Francisco used laboratory cultures of neurons to study how the antibiotic, minocycline, might protect neurons.9 In a study published in Proceedings of the National Academy of Sciences, they showed that minocycline inhibits PARP-1, a protein that responds to DNA damage by promoting inflammation and cell death. They concluded that minocycline’s inhibition of PARP-1 may confer its anti-inflammatory and neuroprotective effect.
Minocycline’s ability to inhibit inflammation and protect neurons might have some clinical benefit, and studies in animal models of Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) have had promising results. The results of a preliminary clinical trial published in Neurology suggested that minocycline might be a candidate for further clinical trials in Parkinson’s disease.10 Clinical trials are also under way to study minocycline in Huntington’s disease and ALS.
The Genetics of Parkinson’s Disease
Familial Parkinson’s disease represents about 10 percent of cases of the disease, and mutations in at least five genes are known to be involved in inherited forms of the disorder. By studying these genes, researchers have gained insights into the disease process, which might benefit all Parkinson’s patients.
Two studies published in Nature examined the relationship between two different genes implicated in inherited Parkinson’s disease.11, 12 The genes, called parkin and PINK1, were shown to work together to maintain the function of mitochondria, the power plants of the cell. These studies and others provide further evidence for the longstanding belief that defects in mitochondrial function could contribute to Parkinson’s disease.
The association of parkin and PINK1 mutations with Parkinson’s disease was first described in individuals in whom both copies of the parkin gene or both copies of the PINK1 gene were defective. Although people with a single defective copy may pass it on to their children, the clinical significance of having one defective copy was unclear. A pair of studies published in Archives of Neurology and one published in Movement Disorders showed that a single defective copy could affect the development of Parkinson’s disease.13-15
People with just one defective copy of PINK1 had a higher risk of developing Parkinson’s disease than their relatives with two normal copies of the gene. Similarly, people with one defective copy of parkin developed Parkinson’s disease at a younger age than most people who develop the disease, including relatives with two normal copies. Because having one defective copy of a gene is much more common than having two defective copies, these mutations may affect more people than previously thought.
Monitoring and Treating Huntington’s Disease
Huntington’s disease is a genetic disorder that develops in adulthood, usually between ages 40 and 50. It is characterized by progressive, uncontrolled movements; emotional disturbances; and loss of intellectual function.
Each child of a parent with Huntington’s disease has a 50 percent chance of inheriting the disease gene, and a test can now predict with high accuracy whether a person has indeed inherited it. But many at-risk people choose not to be tested because there is no cure, no means of prevention, and few effective treatments for symptoms.
A potential way to monitor both the progression of the disease and effectiveness of possible treatments may be provided by monitoring immune “microglial” cells. These cells may contribute to the disease by becoming activated and secreting inflammation-promoting substances. A group of investigators led by Paola Piccini used positron-emission tomography to show that the level of microglial activation correlates with the severity of Huntington’s disease. These findings, published in Neurology, support a role for microglia in the disease.16 The findings might pertain to other neurodegenerative disorders as well.
A potential treatment for Huntington’s disease is glial-derived neurotrophic factor, or GDNF. It can protect nerve cells and even promote their regrowth. Despite the earlier discontinuation of a major clinical trial in humans of GDNF, smaller studies in 2006 looked at GDNF as a treatment for Parkinson’s disease, with varying results.17-19 GDNF was also used to treat Huntington’s disease in a mouse model in a study published in Proceedings of the National Academy of Sciences.20 Researchers led by Jeffrey Kordower used a virus to deliver GDNF into the brains of the mice, resulting in behavioral improvements, fewer dead nerve cells, and fewer inclusion bodies. Further studies are needed to determine if GDNF can be an effective treatment for Huntington’s disease in humans.
Although there are currently no therapies to treat the underlying disease process, drugs that alleviate the symptoms of Huntington’s disease may improve the quality of life for these patients. A clinical trial of one such treatment was reported in Neurology.21 In this 12-week study, patients who received a drug called tetrabenazine had a significant reduction of uncontrolled movements when compared to patients who received a placebo.