© Royalty-Free / Corbis

The most active research on movement disorders in 2005 continued to be in the area of genetics, and studies in the clinic and laboratory have revealed new treatments, refined current treatments, and led to new ways to deliver drugs to the brain. Researchers also studied the cellular and molecular changes associated with movement disorders to learn more about their causes.

Spotlight on Gene Mutations

In the past decade, technological breakthroughs in genetics have opened new doors to understanding human diseases. Parkinson’s disease is no exception. At least five genes have recently been identified in families with Parkinson’s. Although familial Parkinson’s makes up only a small proportion of cases, insights from studying these genes and their protein products have advanced scientists’ understanding of the disease process.

For example, genetic studies helped uncover the causative role of the alpha-synuclein protein and the protective role of the parkin protein in Parkinson’s disease. Alpha-synuclein is a major component of Lewy bodies, protein deposits typically found in the neurons of Parkinson’s patients. Parkin is believed to protect against the disease by suppressing the action of the toxic alphasynuclein or by causing the deposits to be degraded and eliminated by the cell.

Two studies published in late 2004 associated mutations in the gene called LRRK2 (leucine-rich repeat kinase 2) with Parkinson’s disease.^1,2 In 2005, a flurry of research, including three studies published in the Lancet and three published in Neurology,^3–8 linked LRRK2 mutations with the disease in many families, and also in sporadic (nonfamilial) Parkinson’s.

Patients who have Parkinson’s and LRRK2 mutations exhibit disease that is clinically similar to typical Parkinson’s, with an age of onset ranging from 28 to 88.In addition, the most common version of this mutation, G2019S, occurs in about 5 percent of familial Parkinson’s cases and 1 percent of sporadic cases. G2019S substitutes a single amino acid in a usually extremely stable part of the gene. Patients who have Parkinson’s and LRRK2 mutations exhibit disease that is clinically similar to typical Parkinson’s, with an age of onset ranging from 28 to 88. The pathology of LRRK2-associated Parkinson’s can vary, particularly with regard to the presence of Lewy bodies. As reported in the March issue of Annals of Neurology, positron emission tomography scans of patients with the G2019S mutation in LRRK2 show a pattern of decreased dopamine synthesis similar to that seen in patients with typical, nonfamilial Parkinson’s disease.⁹

The protein the LRRK2 gene makes was named dardarin, after the Basque word dardara, meaning “tremor.” The action of dardarin is unknown, but mutations in the gene might result in activation or inactivation of dardarin, or may change how it interacts with other proteins. Dardarin mutations might also increase susceptibility to Parkinson’s by promoting the formation of protein aggregates or making nerve cells more vulnerable to degeneration.¹⁰

Although no mutations were detected in thousands of unrelated, unaffected control subjects, some family members of patients with Parkinson’s had LRRK2 mutations but showed no sign of disease, and many patients with Parkinson’s had LRRK2 mutations but reported no family history of the disease. This indicates that other influences, either genetic or environmental, are probably involved in Parkinson’s development. Increasing age, already known to be a risk factor for the disease, may be one of those influences that favors the development of the disease when the LRRK2 mutation is present. The frequency with which the presence of the mutation is associated with disease increases with age. In a study published in the American Journal of Human Genetics, 17 percent of subjects with the mutation had Parkinson’s disease at age 50, while 85 percent of subjects with the mutation had symptoms at age 70.¹¹

LRRK2 mutations may be the most common mutation associated with Parkinson’s disease. Some have proposed that genetic testing for LRRK2 mutations could be useful in the clinical setting because LRRK2 mutations may be present even without a family history of Parkinson’s. Such testing raises ethical issues, however, because no treatment prevents the disease and genetic testing provides no direct medical benefit. 

A buildup of alpha-synuclein in neurons is characteristic of Parkinson’s disease, but the normal job of alpha-synuclein is unknown and the connection between its aggregation and neurodegeneration is unclear.

Gumming Up the Works

A buildup of alpha-synuclein in neurons is characteristic of Parkinson’s disease, but the normal job of alpha-synuclein is unknown and the connection between its aggregation and neurodegeneration is unclear. In the June 17 issue of the Journal of Biological Chemistry, Chang-Wei Liu and colleagues describe how alpha-synuclein aggregation may occur in a cycle that is toxic to cells.¹² In their experimental model of Parkinson’s, normal alpha-synuclein unfolds and is incompletely degraded. This leaves fragments of alpha-synuclein, which serve as “seeds” to initiate buildup of the full-length protein. The accumulation inhibits the cell’s protein-degradation system, compounding the accumulation with both more fragments and full-length protein. The cycle continues, eventually killing the cell.

A protein accumulates In Parkinson’s disease, a protein called alphasynuclein may collect within neurons as part of a cycle that eventually kills the cells. Diagram courtesy of Dr. Harry Baker

Deposits of alpha-synuclein also are found in the brains of patients with a disorder called multiple system atrophy, which can cause Parkinson’s-like symptoms, as well as dizziness, speech problems, and dementia. In this case, alpha-synuclein aggregates are predominantly found not in neurons but in oligodendrocytes, cells that make myelin, the insulating covering around the axons of neurons. In the March 24 issue of Neuron, Ikuru Yazawa and colleagues reported that they had produced the first mouse model for multiple system atrophy by overproducing alpha-synuclein in oligodendrocytes.¹³ This model should improve the understanding of the effects of alpha-synuclein aggregation on multiple system atrophy and may allow researchers to develop new treatments. 

Continued Interest in GDNF

The search continues for new treatments for Parkinson’s disease. Levodopa, an amino acid that helps form dopamine, is currently the most effective treatment for the disease, but its effectiveness lessens over time and it can cause side effects such as dyskinesia (uncontrolled movements). Furthermore, levodopa treats only the symptoms of Parkinson’s; it has no effect on the degenerative process. Research in animal models has shown that a substance that nourishes neurons, called glial cell line–derived neurotrophic factor (GDNF), can protect or even restore the dopamine-producing neurons that are damaged in Parkinson’s disease.

Unlike levodopa, GDNF cannot easily get through the tight mesh of blood vessels in the brain, called the blood-brain barrier, which is why, in recent clinical trials, the drug was delivered directly into the brain via catheter. The studies were terminated because of disappointing results, but interest in GDNF remains high. One reason for optimism is a report in Nature Medicine that regrowth of nerve cells was discovered in the postmortem exam of a man who had participated in a GDNF trial and later died of unrelated causes.¹⁴ This was the first time any reversal of damage in Parkinson’s disease had been demonstrated in humans.

Another way to deliver GDNF where it is needed is to implant GDNF-producing cells into the brain. The carotid body is a small structure in the carotid artery that senses changes in blood gases and helps regulate breathing. Cells in the carotid body also produce dopamine and GDNF. Javier Villadiego and colleagues used a mouse model for Parkinson’s to demonstrate that receptor cells within the carotid body—called glomus cells—produce large amounts of GDNF for a prolonged period after transplantation.¹⁵ They proposed that these glomus cells might be used to deliver GDNF to the brains of Parkinson’s patients.

Gene therapy presents another possible treatment using GDNF. The gene for GDNF can be incorporated into a harmless virus and injected into the brain, where the virus infects cells and causes them to produce GDNF. Andisheh Eslamboli and colleagues used this approach in a primate model for Parkinson’s disease and reported their findings in the January 26 issue of the Journal of Neuroscience.¹⁶ Dopamine-producing nerve cells were protected by the treatment, and the monkeys showed behaviors that indicated recovery of motor function. 

More Uses for Gene Therapy

Because the side effects of levodopa may be caused by rising and falling levels of the drug between doses, gene therapy has been proposed as a treatment to be used along with or instead of levodopa to provide more continuous, consistent levels of dopamine to the brain. Thomas Carlsson and colleagues used gene therapy in a rat model of Parkinson’s, delivering the genes for two enzymes that work together to make dopamine.¹⁷ The treated rats showed reduction in both Parkinson’s-like behaviors and levodopa-induced movements.

Experiments with genes can suggest new strategies for gene therapy, as Masanori Yamada and colleagues reported in the February issue of Human Gene Therapy.¹⁸ By introducing the gene for alpha-synuclein, they induced PD-like motor dysfunction in rats. If they delivered the gene for parkin at the same time, the dysfunction was lessened, presumably because parkin can suppress the action of, or eliminate, the alpha-synuclein deposits. 

Fine-Tuning Deep Brain Stimulation

Deep brain stimulation (DBS) uses surgically implanted electrodes to relieve symptoms of Parkinson’s disease, essential tremor, and dystonia (abnormal muscle tone) by delivering pulses of electricity to specific areas of the brain. In studies published in Archives of Neurology in 2005, researchers investigated ways to make deep brain stimulation more effective.

Electrodes to the rescue Deep brain stimulation has been effective at relieving symptoms of movement disorders. Researchers are fine-tuning the technique, which involves placing electrodes in the brain that deliver electric pulses to specific brain regions. Photograph courtesy of the Cleveland Clinic

One study included 41 patients who had unsatisfactory results after DBS.¹⁹ Outcomes were improved in more than half of the cases by replacing misplaced electrodes, reprogramming the device, or adjusting medications. Because DBS is being performed more frequently every year, the authors stressed the need for post-surgical follow-up and for more effective presurgical screening to determine which patients are likely to have successful outcomes.

Another study in Archives of Neurology focused on the placement of DBS electrodes by comparing the two most common sites for DBS electrodes in PD, the globus pallidus interna (GPi) and the subthalamic nucleus (STN).²⁰ Overall, both placements were equally effective, although STN stimulation was better than GPi stimulation at alleviating very slow movement (“bradykinesia”). Cognitive and behavioral complications occurred only with STN stimulation. An accompanying editorial in the journal suggests that, although more research is needed, electrode placement in DBS may eventually be targeted to meet each individual patient’s needs.²¹ 

Mice Yield New Clues in Huntington’s Disease

No effective treatment exists for Huntington’s disease, which is caused by mutations that tack extra amino acids onto the end of a protein called huntingtin. Mutant huntingtin seems to cause disease by collecting within nerve cells. The longer the chain of added amino acids, the earlier in life the disease begins. Mouse models for Huntington’s disease have been produced that express mutant huntingtin, and several labs have used these models to reveal the cellular and molecular events that lead to Huntington’s and to investigate potential treatments.

Mutant huntingtin activates an important regulatory gene called p53, which, in turn, activates many other genes, ultimately resulting in cell death. Inactivation of the p53 gene in a mouse model for Huntington’s disease prevents the abnormal behaviors of the mice.²² Interestingly, p53 is inactivated in many cancers, and the lower incidence of cancer in patients with Huntington’s may have to do with the effects of high levels of p53.

Mouse models also have revealed that mutant huntingtin may cause disease by impairing cell-to-cell interactions within the brain and altering normal calcium levels in neurons.^23,24 Several drugs have been identified that can prevent cell death in the laboratory by correcting calcium levels. In the April 19 Proceedings of the National Academy of Sciences, Scott Q. Harper and colleagues reported the successful treatment of a mouse model for HD.²⁵ They used a technique called RNA interference to inhibit production of mutant huntingtin, which resulted in near-normal behavior. Together, these findings provide hope that treatment for humans with Huntington’s disease may indeed be possible.

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