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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.

 

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