The Johns Hopkins Morris K. Udall Parkinson's Disease Research Center of Excellence has led the world in explaining fundamental aspects of the neurodegenerative disease. Named in memory of Arizona Congressional Representative Morris K. Udall, who died from a Parkinson's disease, the Center at Johns Hopkins was handpicked by the National Institutes of Health as one of three sites to research and fight the disease.
The Institute for Cell Engineering
One of the most exciting aspects of working at Johns Hopkins for scientists has always been the fact that they are surrounded by stars in their field, both in research and medical care. That means basic science discoveries in Parkinson's disease never take place in isolation. Instead, the relationship between researchers and physicians is designed to translate advances in the lab into therapies for patients.
The Institute for Cell Engineering (known as ICE), established in 2001, brings together top-level scientists in a range of disciplines who are advancing efforts in three highly promising areas: stem cell therapy, nerve regeneration, and immunotherapy. This tremendous resource, the first of its kind on an academic campus, offers an unprecedented opportunity to develop cures for neurological conditions - - from spinal cord injury to ALS (Lou Gehrig's disease).
While ICE aims to change the outlook for several neurological diseases, the new technologies it also hopes to foster will depend on expanding fundamental knowledge. "As we learn the basic biology of stem cells, we still have to learn how to 'instruct' them to become particular cells such as dopamine neurons", says physician Ted Dawson. "We need to understand how to direct supporting cells like astrocytes to take care of new neurons."
Because Parkinson's involves the selective degradation of a single population of nerve cells, it will be among one of the ICE's early research targets. "It's a disease that presents a very attractive first step for investigation," Dawson says.
What Makes a Protein Toxic?
Studying Parkinson's presents an immediate obstacle: It's impossible to observe molecular events as they are taking place in patients. "That's why it becomes enormously helpful to have models of the disease," explains neuropathologist Michael Lee. The discovery in 1998 of a Parkinson's gene provided Lee with the right tool for engineering the first "transgenic" mouse to create such a model. These mice now possess the mutation -- an alteration in the gene that codes for the protein alpha-synuclein -- that exists in humans who have the familial form of Parkinson's.
That particular protein, alpha-synuclein, had long been part of another mystery. Researchers have been aware that people with Parkinson's develop a peculiar abnormality in the brain: the presence of dense protein aggregates called Lewy bodies. Those protein clumps include alpha-synuclein. No one knows whether these aggregates are a cause or a result of the destructive process. What's clear is that their presence is an indication of the disease.
Because Lee's specialized mice could produce an abundance of the abnormal protein, he had a new window on the degenerative process. He was able to observe molecular changes taking place as the Lewy bodies were forming. What he found has turned out to be fundamental to the disease process: the mutated protein chains undergo an abnormal physical alteration in which one end is chopped off inside the neurons. It was that division, Lee realized, that caused the protein to clump and become toxic to cells.
Not only does Lee's discovery suggest how alpha-synuclein becomes a killer of cells, it also draws ties to the protein destruction that occurs in Alzheimer's disease as senile plaques are formed.
The next step will be to track down the enzymes responsible for the unkind cuts. The payoff could be huge. "If the division plays a role in making alpha-synuclein toxic," Lee explains, "we may not be all too far from developing drugs to inhibit that step. In theory, that will leave the protein harmless -- and the damage would never take place."
Why Cells Die
Resilient and adaptable, the cells of our body are meant to survive as long as we do. Each cell contains an entire armament of tools to repair or even replace itself after an injury. Yet, in Parkinson's disease, a select population of dopamine-producing cells in the brain begins to die, undergoing the programmed steps of cell death known as apoptosis. The lab of Valina Dawson has taken on the study of this death cascade. The rationale: "If we can identify the biochemical steps involved in the process," she says, "we may be able to provide new targets for drug intervention. We may be able to break the chain."
Dawson's lab has made some of the most important advances to date in the description of this process. Her group has identified a number of death effectors, or proteins that help a cell make the decision about whether to begin to self-destruct. One molecule, call PARP, acts as a white flag of surrender, signaling destructive enzymes that a cell is beyond repair in cases such as stroke and Parkinson's. The Dawson team has already developed and licensed several PARP inhibitors that may become tools to interrupt the downward spiral.
The flip side of studying the death cascade is understanding what exactly cells have in their armament that enable them to survive. "It may be we can enhance the survival process of dopamine neurons," Dawson says. Cardiologists are well aware of the cellular phenomenon called "preconditioning" in which severely damaged heart cells are able to produce survival factors that make nearly dead cells bounce back. Dawson's lab is unraveling the genetics of preconditioning, a complicated array of at least 30 genes, and has developed remarkable new DNA-combing technology to find them.
All of this information will be useful in the engineering of cells for neuronal replacement, which is the ultimate therapy. "But we're not quite there yet," Dawson says. "There still are a lot of questions ahead."
Clinical & Laboratory Research In Progress
- Identification of genes for PD and other Parkinsonian syndromes
- Development of genetically engineered mouse models of PD and other Parkinsonian syndromes -- our best tools to understand the cause and test new therapies
- Studies of the basic cell processes underlying PD-triggered death of dopamine neurons
- Studies on the sequential steps on the path to cell death in PD, using animal, culture and test tube models
- Use of state-of-the-art genomic and proteomic strategies to understand how genetic mutations result in familial PD
- Identification of the clinical and pathologic correlates of PD and PD-like syndromes
- Neuroprotective and therapeutic drug trials
- Clinical Trials to treat psychiatric and cognitive aspects of Parkinson's disease
- Identification of methods to improve the recognition of mood disorders in patients with Parkinson's disease
- Elucidating the nature of work- and social-related disability in Parkinson's, and the respective contributions of motor, cognitive, and psychiatric aspects of the disease
Clinical & Laboratory Research In Development
- Elucidating and identifying novel pathways of neuronal survival and identification of new therapies
- Understanding the role of synaptic dysfunction, protein turnover and inflammation in dopamine cell death
- Clarifying how dopamine neurons and neighboring cells develop normally, as a basis for understanding PD pathology and stem cell therapy
- Identifying biomarkers for early diagnosis and monitoring efficacy of neuroprotection or neurorestorative trials
- Developing additional genetically engineered mouse as well as invertebrate models of PD and other Parkinsonian syndromes
- Developing new biology-based tools, including bioassays, to screen thousands of potential therapies in a record time
- Exploring the use of stem cells -- adult, embryonic and all varieties in-between -- pinpointing those most likely to retard or reverse dopamine cell loss
- Developing therapies that encourage dopamine neuron growth: speeding growth of axons in still healthy neurons and, if feasible, hastening the meeting of stem-cell-derived dopamine neurons and the striatum
- Developing drugs that protect dopamine neurons and slow down their rapid degeneration in the disease, taking advantage of current theories of PD cell death
- Bringing together large pharmaceutical companies and biotechnology firms to develop bioassays and drug therapies based on transgenic (human-gene-carrying) cell, tissue and organ models of PD