U.Va./MitoKor Research Team Issues Report: Genetic Defect May
Point to Heredity as a Source of Parkinson's Disease
08:30 Oct 11, 1996

CHARLOTTESVILLE, Va., Oct. 11 /PRNewswire/ -- A specific genetic
defect that may cause Parkinson's disease has been identified by
scientists at the University of Virginia and MitoKor, a
California-based biopharmaceutical company, according to a study
published in the October issue of the Annals of Neurology.

"There is a piece of DNA that doesn't play by the rules," said W.
Davis Parker, professor of neurology at U.Va. and leader of the
research team. "The genes contained on mitochondrial DNA
(mtDNA) exist independent of nuclear DNA. In other words, this is
a new principle of human genetics that may explain why some
diseases currently thought of as sporadic, like Parkinson's, may
in fact be inherited in an unorthodox way."

The scientists found that the genetic defect affects a
mitochondrial enzyme called complex I. Although scientists have
suspected for the past seven years that the complex I defect is
a key factor in the onset of Parkinson's, they did not know the
origin of the defect. The U.Va/MitoKor team found that the
complex I defect arises from mitochondrial DNA and interferes with
the function of mitochondria -- thousands of thread-like bodies in
each cell which contain enzymes for the production of energy.

"Complex I, which is abnormal in Parkinson's patients, is a
bioenergetic enzyme that serves as the principal starting point
of the electron transport chain, the energy generating mechanism
found in the mitochondria of each cell," said Robert E. Davis,
chief executive officer of MitoKor and a co-author of the study.
"We believed that a mitochondrial rather than a nuclear genetic
mechanism was at work in Parkinson's."

To test the theory, the researchers developed proprietary cybrid
(cytoplasmic hybrid) cell lines to model the mitochondrial DNA of
Parkinson's patients. First, human neuroblastoma cells --
embryonic cells derived from the neural tube that give rise to
neurons -- were depleted of all their mtDNA. Mitochondrial DNA from
24 Parkinson's patients was then transferred into those cells, the
resulting cell lines were cultured. Cybrid cell lines possessing
mtDNA from 28 non-Parkinson's patients were used as the normal
controls.

The scientists then performed a series of biochemical assays on
the cybrid cell lines, measuring cytochrome oxidase activity and
complex I activity, the key elements within the mitochondrial
electron transport mechanism. They also analyzed for the production
of oxygen radicals and the effects of a parkinsonism-inducing toxin
called MPTP, a contaminant of an illegally prepared heroin-like
narcotic.

Complex I activity was 20 percent lower in the Parkinson's disease
(PD) cybrids as compared to the controls.

Additional research demonstrated that the genetically encoded
complex I defect of Parkinson's disease serves as a source of
oxygen radical generation. Oxygen radicals are widely believed to
play a role in the death of neurons in neurodegenerative diseases
like Parkinson's, Alzheimer's and amyotrophic lateral sclerosis
(ALS or Lou Gehrig's disease).

Also, cells containing Parkinson mtDNA were more susceptible to
an MPTP derivative.

This indicates that even though the enzyme defect is genetic,
environmental toxins could still contribute to the disease's
development.

"While the genetically determined complex I defect in Parkinson's
disease may itself be sufficient to produce the disease, our research
does not rule out the importance of external toxins in the disease
process," said Dr. Russell Swerdlow, U.Va. neurologist and lead
author of the study.

"The observation that a specific biochemical defect can render cells
more vulnerable to MPTP toxicity illustrates how interactions between
an environmental mitochondrial toxin and an apparent mtDNA defect
could accelerate neurodegeneration. This may explain why some
individuals develop Parkinson's disease following toxin exposure,
while others similarly subjected to the same toxin at the same
dose do not."

The U.Va./MitoKor team's next step will be to characterize the exact
mtDNA mutations that may lead to Parkinson's disease. "We are
conducting further mutational analysis of the mtDNA of
Parkinson's disease patients," Davis said. "Once the defect or
defects are known, we'll be working to develop a therapeutic agent
that reverses the complex I defect."

MitoKor, a development-stage biopharmaceutical company in San
Diego, Calif., is the only company in the United States whose sole
focus is the role of mitochondria in human disease. Their
proprietary technology is leading the way in the commercialization
of pharmaceutical and diagnostic products targeted to treat
Alzheimer's, Parkinson's, diabetes mellitus (NIDDM) and schizophrenia.
MitoKor was formed in 1992 under the name Applied Genetics.

SOURCE MitoKor

Copyright 1996, PR Newswire
John Cottingham    To search the Parkinsn archive, send search requests
                   to [log in to unmask] with Archive Search as the subject.
LibraryH           Searches of the Subject: line, From: line and Body are
                   possible. Look for "Revised Current Topics...." message
[log in to unmask]    for Articles and Studies available by e-mail.