Scientists have made real progress in understanding the causes of
Parkinson's disease (PD) in the past decade. Several genes have been
discovered that either cause PD or increase the likelihood of
developing it, and further knowledge has been gained about
environmental toxins that increase the risk of PD. Significantly, a
clearer picture is emerging of exactly how cells die, which is laying
the groundwork for developing treatments to slow or prevent the death
of vulnerable brain cells.

Parkinson's disease is a neurodegenerative disease, meaning it is
caused by progressive degeneration and death of neurons, or brain
cells. Other neurodegenerative diseases include Alzheimer's disease
and Huntington's disease. In Parkinson's disease, neurons in a part
of the brain called the substantia nigra die off. The loss of these
cells causes the symptoms of the disease.

While much remains to be learned, the picture that is emerging
indicates that PD develops when genetic susceptibility combines with
environmental triggers. The substantia nigra neurons may become
unable to cope with normal levels of excitation, and abnormal
proteins may build up within the cell. The brain tissue that
surrounds these cells may become inflamed, leading to additional
problems. In his Presidential Lecture at the American Academy of
Neurology's 55th Annual Meeting in Honolulu, Stanley Fahn, MD,
presented an overview of some of these new developments in the
understanding of Parkinson's disease. Dr. Fahn is Director of the
Center for Parkinson's Disease and Other Movement Disorders at
Columbia University, and is one of the most respected leaders in the
world in the field of Parkinson's disease.

The Importance of a Gene Called 'Parkin'
A gene called parkin has generated a great deal of excitement in
recent years. The parkin gene was first implicated in early-onset PD,
in which symptoms begin as early as age 30. This gene was originally
thought to only be responsible for disease in people who inherited
two defective copies of this gene. This type of inheritance pattern
is called "autosomal recessive." More recently, Dr. Fahn said, it has
become clear that mutations (abnormal changes) in the parkin gene are
found in many people with typical late-onset PD (though this still
represents only a small fraction of all PD patients). A study
published during 2002 described 35 patients with PD who had parkin
mutations and whose symptom onset was after age 60. Thirty of these
patients had only one, rather than two, defective gene copies. This
genetic condition is called heterozygosity. This finding may indicate
that the likelihood of developing PD increases with decreasing
function of parkin, so that two defective genes leads to early onset,
while one defective copy leads to late onset.

"Probably more cases are gene-related than we had previously
appreciated," Dr. Fahn said. "Parkin and the other autosomal
recessive gene mutations need to be closely evaluated in the sporadic
adult-onset PD population. It may be that heterozygous mutations of
these recessive genes could account for many adult-onset sporadic
cases of PD."

What does this mean for people who have PD? Further study will be
needed to assess what proportion of people with typical late-onset PD
carry a single parkin mutation, and it is too soon to tell how great
the increased risk is from such a single mutation. In any event, it
is likely that the mutation only leads to PD in a person also exposed
to other risk factors. As Dr. Fahn states, "The great majority of
cases are of unknown etiology and these are suspected to be due to a
combination of both genetic and environmental factors."

Misfolded Proteins and Toxic Protofibrils
Parkin's normal function also provides a clue to the molecular events
underlying cell death in the substantia nigra, the part of the brain
that degenerates in PD. Proteins in all cells must fold up into the
right shape in order to function, and misfolded proteins can cause
trouble. The parkin protein normally helps the cell dispose of
misfolded proteins. A growing body of evidence indicates that defects
in this protein "disposal system" may be a central step in the
development of PD.

One protein that is often misfolded, even in people who do not
develop PD, is alpha-synuclein (AS). Dr. Fahn explained that unless
misfolded AS is quickly disposed of within the brain cell, it may
link up with other AS proteins to form structures within the cell
known as "protofibrils." New research indicates these protofibrils
may be toxic. These fibrils may cause damage by puncturing the little
sacs inside the cell that contain dopamine. Dopamine is a
neurotransmitter, a chemical released by one neuron to stimulate
another. Substantia nigra neurons produce large amounts of dopamine,
which they must store before releasing it, in order to prevent it
from damaging the inside of the cell.

The AS protofibrils are stabilized in the presence of a breakdown
product of dopamine, called dopaquinone. Stabilization prolongs their
toxic effect, further damaging the cell. According to this model,
then, accumulation of AS (due to a protein breakdown defect),
combined with dopaquinone (which is found wherever dopamine is made),
creates a toxic environment for the cell. If this model is correct,
it helps explain why substantia nigra neurons are so vulnerable-they
are one of the main producers of dopamine in the brain. "This model
explains the selective toxicity of alpha-synuclein," Dr. Fahn said.

Inflammation: Making a Bad Situation Worse
Inflammation, which is the body's response to tissue damage, is known
to occur in the brain of patients with PD. "Inflammatory changes are
not primarily responsible for PD," said Dr. Fahn, "but may aggravate
its pathogenesis, and anti-inflammatory drugs may have potential as
treatments." A new study indicates that so-called COX-2 inhibitors,
which inhibit inflammation, can also directly inhibit production of
dopaquinone, indicating they may have a dual mechanism of therapeutic
action in this disease. (COX-2 inhibitors are currently being used to
treat arthritis.)

"Several pathogenetic mechanisms appear to be playing a role in the
development of PD, and they interrelate with each other," Dr. Fahn
said. "Attempts to slow the progress of PD will likely be more
successful if multiple targets can be attacked simultaneously."

It is too soon to know if COX-2 inhibitors, or any other agent, will
actually help slow PD. Selegiline, commonly used for PD symptoms, has
also been examined for its potential to slow PD progression. Despite
more than a decade of study, no firm answer to this question is in
hand. Other agents currently being examined to see if they can help
slow down disease progression include coenzyme Q10, an antibiotic
called minocycline, and a drug called rasagiline (which is also used
to treat the symptoms of PD). People with PD may be able to enroll in
a clinical trial testing the long-term safety and effectiveness of
such agents. Interested individuals should discuss this with their
neurologist