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Bench Research

Ravi Thomas

Ravi Thomas sets up a PCR plate with the PD and control brain cDNA samples.

The basic research arm of the Virginia Commonwealth University Parkinson’s and Movement Disorders Center is housed in the state-of-the-art Hermes A. Kontos Medical Sciences Building on the university’s MCV Campus. The scientists comprising the center's core research group have been a cohesive team for a number of years. Working together, our scientists have conducted extensive investigations into the causes of neurodegenerative processes and effects on the central nervous system of Parkinson’s patients.

While there is much experimental work still to be done in validating the therapies described below, the staff of the research division is also continuing to study the energetic and signaling mechanisms of neurons looking for further clues as to why these cells die and how the process can be stopped.

 

Studies of human neurons that make Lewy bodies

Lewy bodies (LB) are spherical inclusions of proteins found inside the nerve cells in brains donated by individuals with Parkinson's disease (PD). The longer an individual has PD, in general the more LB’s that are formed. Parkinson's patients with dementia have LB’s throughout the brain, particularly in the areas that regulate emotion, memory, planning and judgment.

Dr. Patricia Trimmer and colleagues have produced several human nerve cell lines that produce Lewy bodies and mimic what is found in PD brain nerve cells. Dr. Knarik Arkun, a VCU Neuropathologist, and Dr. Ann Rice were able to isolate neurons from the substantia nigra of human brains donated to our Brain Tissue Resource Facility. They conducted this study in brains from persons who had Parkinson’s disease and found that the neurons containing Lewy bodies were “healthier” in terms of their mitochondrial energy producing capacity than neurons that did not have Lewy bodies.   This suggests that Lewy bodies might be protective in these nigral neurons.

We can now compare our Lewy body-producing human cell lines made from living PD patients with Lewy body-containing neurons isolated from brains of persons who died with PD to determine whether our cell lines mimic this apparently beneficial effect of Lewy bodies. So far our work indicates that some of these cell lines (“cybrids”) made from PD patients share the property of increased mitochondrial energy producing capacity.

Measuring the complex control of how energy is made in PD brains

The human brain comprises 2-3% of body weight but uses 20-25% of the oxygen, mainly to make energy. This energy-intense organ relies on large numbers of mitochondria to make the energy. Mitochondria are double-walled organelles that are essential for proper energy production in nerve cells. Nerve cells cannot function normally and can die if they don’t make enough energy, and nerve cells have a complex “signaling” program that regulates their mitochondrial mass. PMDC investigators have published several papers about how the signaling system for regulating mitochondrial mass (“mitochondrial biogenesis”) is not regulated normally in Alzheimer’s disease (AD) and Parkinson’s disease (PD) brains. As a result, AD and PD brain tissues have defective energy production and suffer from increased damage from oxygen radicals (“free radicals”). These findings are important therapeutically because:

  1. PMDC investigators are helping to develop a unique gene therapy that stimulates mitochondrial biogenesis and energy production in brain. This engineered naturally occurring protein appears to be very safe and has been extensively tested in older animals. With further development, this therapy could be applied to PD subjects to improve nerve cell function and likely slow disease progression. PMDC investigators are partnering with a minority-owned, Virginia small business to develop this therapy.
  2. Using our laser capture microscope to isolate individual nerve cells from human brain and spinal cord tissues, PMDC investigators have shown that mitochondrial energy producing capacity is decreased in Alzheimer’s brains and ALS (“Lou Gherig disease”) spinal cords. In the coming year we will be using the latest RNA sequencing technology (“next generation sequencing”) to study gene expression patterns in these nerve cells. We are also starting a similar project to study gene expression patterns in nerve cells that die excessively in Parkinson’s patients who develop dementia.

Generating human stem cells and neurons from blood samples

Paula Keeny

Paula Keeney demonstrates the use of an Odessey Infra Red Scanner, an instrument used to detect the final labeled proteins in a Western or Immuno Blot.

The ability to produce inducible pluripotential stem cells (iPSC’s) from patient samples both bypasses the complex ethics of embryonic stem cell research and allows for the creation of cell lines from patients with specific diseases. The iPSC’s generated from Parkinson's patients and patients with other degenerative diseases can be turned into nerve cells, that can then be studied in the laboratory. PMDC investigators are in a unique position to determine how these stem cell-derived nerve cells resemble nerve cells in brains of persons who died with PD or other degenerative conditions. This is a very important path to pursue. If the derived nerve cells resemble nerve cells found in disease brains, then we will have an excellent model to:

  • Determine how nerve cells get sick and die
  • Create advanced models of neurodegenerative diseases (“brain disease in a dish”)
  • Test drugs on a reliable platform. This last point is crucial because available cell and animal models of degenerative diseases have failed repeatedly to predict whether a drug can slow the progression of disease in humans.
  • We have made extensive progress over the last year. Thanks to a generous anonymous donation we were able to outfit our stem cell lab to produce iPSC’s. We have been successful and are now turning the iPSC’s into neurons. We have established a collaboration with investigators at Northwestern University to obtain a genetic tool that will allow us to create special nerve cells from iPSC’s that are representative of the neurons that die in Parkinson’s patients who get dementia.

    Neuroprotective drugs

    Dr. Bennett moved a novel neuroprotective drug from experiments in his lab to clinical testing in patients with Lou Gehrig’s disease, or ALS — a devastating, incurable disease with no treatment. Following promising initial clinical studies, Knopp Neurosciences, a small biotechnology company, licensed the drug in 2006 and is pursuing commercial development for ALS.

    In December 2009, Knopp presented very promising results from their studies and have recently partnered with a larger pharmaceutical company to conduct a large trail that will satisfy Food and Drug Administration requirements for drug effectiveness.

    Bennett also retained capacity to study the drug independently of Knopp and plans to initiate a study in Parkinson’s patients at the McGuire VA Medical Center and VCU Medical Center. These studies will be small population size and time-limited to see if the drug is well-tolerated and has any effect on Parkinson’s symptoms. An effective neuroprotective drug in Parkinson’s will not treat symptoms, so having no effect on Parkinson’s symptoms will be a good outcome. Based on initial findings, the next step will be to select a larger population and longer term study to determine if the drug slows the disease progression.

     

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