Underlying causes
A Glimpse into the Latest Research on Parkinson's
Disease
by Lisa Melton, PhD
For more than a century, scientists have been arguing about what
causes Parkinson's. The mystery of what causes the particular nerve
cells in the substantia nigra to die has yet to be solved. Aging is
the prime risk factor for Parkinson's and a third of the brains of
people over 90 years show the changes of Parkinson's. Studying
normal and Parkinson's brains from individuals of all ages through
brain tissue research is a most important way to find out about the
disease process. The PDS funds a Parkinson's Brain Bank dedicated to this
type of research at Imperial College in London.
Environmental and genetic factors are key areas of research into
the cause of Parkinson's. Most scientists agree that a combination
of genes and the environment conspire to trigger the disease,
though exactly which genes and which external insults is still not
clear. Teasing them out is important as it may help to prevent the
disease in the first place, as well as guide the development of new
therapies.
Exposure to pollutants and pesticides has been put
forward as a likely environmental insult. Investigations into
incidences of Parkinson's in agricultural communities, for
instance, have repeatedly linked high exposure to certain
pesticides, herbicides and fertilisers with the
disease.
A study in rats published in Nature Neuroscience by
Betarbet(a) points the finger at rotenone in particular. They
found that, in rats, this household insecticide - widely used and
marketed as 'natural' because it is eventually degraded in the
environment - can cause major features of Parkinson's. The
hypothesis emerging from their study is that low levels of noxious
substances - including other pesticides with similar action - may,
over time, instigate a molecular chain of events that eventually
leads to Parkinson's. However many other researchers have had
difficulty replicating the specificity of these findings.
Viruses have been considered a possible cause for parkinsonism
ever since the outbreak of post-encephalitic parkinsonism following
the global epidemic of encephalitis lethargica which occurred
between 1917-1926. Other viruses have been suggested as a
possible cause, but supportive scientific evidence is
lacking(b).
A number of studies implicate iron in the pathology of
Parkinson's. Many consider iron a prime suspect because levels are
high in people with the disease. It is also striking that
Parkinson's afflicts areas of the brain such as the substantia
nigra (its name derives from its black pigmentation), which has
high levels of iron.
The problems start when cells in the substantia nigra begin to
die - probably after an initial toxic insult. The theory is that
iron released from dead neurons begins the chain of events that
lead to oxidative stress. Normally, neurons are shielded from
oxidative damage by keeping iron tightly bound to a substance
called neuromelanin. As soon as iron molecules are set free, they
produce highly reactive free radicals that go on a rampage.
Dopamine-producing cells are particularly vulnerable to oxidative
damage. Antioxidants, discussed earlier in this article, have the
potential to neutralise these free radicals, but at the moment
there is no treatment that is proven to work, although many
promising compounds are currently being tested.
Not everyone is equally predisposed to these toxic insults. It
is possible that the susceptibility of an individual to pesticides
or to free radicals is determined genetically. Mutations in the
genes encoding alpha synuclein and parkin have been
linked to a small number of cases of Parkinson's and are generally
thought to be responsible for some cases of early-onset
Parkinson's. The generation of Parkinson's through these mutations
may however be solely genetic with no environmental interaction
being needed for the condition to develop.
Scientists speculate that for most cases of Parkinson's, it is a
cluster of genes that, acting in concert, define an individual's
vulnerability to environmental agents. Sophisticated techniques to
identify genetic variants linked to diseases already exist, and
soon it should become possible to screen people for genes that
predispose to Parkinson's. However this raises difficult ethical
issues relating to employment and insurance, as well as the anxiety
caused by having knowledge of vulnerability to a condition of
late-age onset.
PDS would like to thank the following for their advice
and comments on this article:
Dr. Roger Barker
Professor Steve Dunnett
Mr. Sam Eljamel
Dr. Richard Grunewald
Professor David Latchman
Dr. Ronald Pearce
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