SECTION ONE
Parkinson's Disease
TOPICS ON THIS PAGE:What is PD?
Types of Parkinsonism
The Brain - Affected Parts
Causes
But is it PD?
YOPD and Genetics
Cell and Neuron
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| LINKS TO: Section Two: Current Treatments | Section Three: Starting Treatment | Section Four: Glossary |
When patients come to see me, I say that if you are going to have Parkinson's, now is a good time
to have it. It's a very active, dramatic time, as there has been a huge
change in the research, knowledge, understanding and treatment of PD in the last five years.
There is a lot of money being pumped into research into PD, with new developments occurring
all the time. These developments consist of a greater insight into
why it happens, plus a greater understanding of the therapeutic aspects of PD. You can take a closer look at PD -
at what happens right down
at cell level, why someone gets PD. Ultimately, if you can find out how a person develops PD, then you might be
able to find out how to treat, cure or even prevent it.
There are examples of this in modern medicine, the best of which is
in the treatment of AIDS. There were a lot of
deaths from AIDS in the 1980s, but not so many in the 1990s. In the 1980s, we did not know
what was going on in AIDS. There were various trials of different medications, and people were dying.
That all changed in the 1990s. The reason for the change was a decision made in the late 1980s to go back and try
to find out why people get AIDS, what happens with the infection, and how does it affect their immune system.
If someone is HIV positive now, they don't necessarily die, as there is now a large variety of medications
available which keeps them alive for years. So, having AIDS is different now to what is was a decade
ago, and having Parkinson's Disease in five to ten years will be different to
having it at the present time, and dramatically different to having it twenty, or even ten years ago.
One of my reasons for being interested in the younger people with PD, from a
research point of view, is that I think the younger
PWPs hold the key as to what happens in PD.
There are five main symptoms:
In the individual dopamine producing cell is found the Lewy Body. We now understand Lewy
Bodies - they are the dustbin of the cell, disposing of excess proteins.
If these cells, which normally chew up excess proteins with great efficiency,
are not working properly, then these clumps of protein start to accumulate within the
cell, and the cell is damaged.
The causes of PD can be divided into two groups - environmental vs hereditary factors. Which
of the two is of
foremost importance has been debated for many years. There have been a number of studies over
the years on this, with variable results. However, there is this intriguing discovery over the years
of families with PD being described - big families, with a lot of people affected. So family members
would say that PD ran in their family. If you can take that at face value, then there must be a
hereditary factor. Some of that was ignored to a certain extent. Other studies found different enzymes
or proteins that may be associated with PD. In studies using the weaver mouse, in whom the
cells in the substantia nigra started dying off soon after birth, and who
therefore starts staggering and developing the symptoms of PD, the mutating gene responsible has
been determined. So there's a lot of interesting data to suggest a hereditary factor in PD, but there
is also a lot of data suggesting environmental factors in it.
So, there has to be that seed that only grows when it lands on fertile soil. Why is that? What
triggers it? There were reports about the risks involved in:
Then there was the story about toxins. A chemist in California was making synthetic opiates in order to make some money,
and somewhere along the way he got his cocktail wrong, and included a toxin known as MPTP. Young heroin addicts using this mixture
developed acute symptoms of PD. This shows that there are toxins out there that, potentially, could cause the symptoms of PD.
This raises the whole spectre that there could be something in the environment that could possibly be causing it.
Initially, in the old literature, the genetic aspect was emphasized first. Then it was the environmental factors,
particularly in relation to MPTP in the
last fifteen years. Then, in the last three to five years, hereditary factors came to the fore again,
because some of the genes that cause PD in some families have been isolated.
It is probably a bit of both. In other words, you probably have to have some genetic
predisposition to it. It is different depending on the age of onset. If you are less than fifty at onset of
symptoms, it is probably due to a genetic factor, much more then than when you are over the age of fifty.
It certainly seems that, when a patient develops PD before the age of fifty, the genetic factor is
the most important one.
The Contursi family changed the whole story of PD in the last twenty to twenty five years. They
brought the whole genetic aspect of PD back up again. The Contursi Kindred are an
Italian family from near Naples, some of whom had emigrated to the USA. Between the two groups, over eighty people
had PD, over six or seven generations. There has been a long study done on this family, and eventually
the gene was isolated.
It was found that a mutation in the gene for a protein called alpha-synuclein
that caused PD in the Contursi Kindred. A closer look at this family's details reveals that there
was a slightly younger age of onset of PD, plus other slight differences, but they are
levodopa responsive, and they do have Lewy bodies. The Lewy bodies are packed with
syneuclein which has accumulated in them.
When I was in New York, our research team looked at about twenty-one families, in an effort to track down the genes
rsponsible. I would like to continue this work in Ireland, as I think we will find that it isn't just
one gene that causes PD. Parkinson's isn't going to be like Huntington's Disease, where one gene is
at fault. I think we will find that Parkinson's may have many, many genes responsible for the onset of PD.
In each of the twenty-one families in our research, we looked at the alpha-syneuclein sequence, and
we discovered that the alpha-syneuclein gene is not commonly responsible even for the familial
form of PD. This was duplicated in other studies. About 10% of PD is familial in origin, and of
that 10%, the
alpha-syneuclein gene is not responsible for all of the incidences of familial PD, and possibly for
as little as 1% of them. So the alpha-synuclein gene is a rare cause of PD. Many genes probably contribute to the development of PD.
It is, however, still important, because if you examine the brains of deceased patients who had PD,
all of then will have alpha-syneuclein staining in the Lewy bodies. So there is something else going on
with alpha-syneuclein in
the brains of people with PD. It is, however, a useful key in opening up doors to get at the majority of
people with PD.
We also studied other families with PD and found no mutations.
Using the New York Brain Bank, we were able to go back and use those portions of a patient's brain that had
been frozen, to find out if there was a mutation of the alpha-syneuclein gene present, or
what was its role. We were
able to study different regions of the brain, to see what that protein was doing there.
In conclusion, we may say that:
If a young person gets PD, there is a long list of other disorders that can mimic it. If someone
develops PD at a young age, when I see them for the first time, I have to make sure that they don't have another
disorder that can mimic Parkinsonism. Other disorders include
In a study done in collaboration with a colleague of mine from Serbia, in a group
of about thirty Young Onset Parkinson's Disease (YOPD) patients (under the age of fifty at diagnosis),
it was found that 6% of their immediate relatives had PD, versus 0.7% of relatives in controls. This
suggests a genetic element.
Autosomal Recessive Juvenile Parkinson's is more common in Ireland than was previously thought.
Because of Ireland's small population and relatively limited gene pool, it is a good location for studying YOPD.
Autosomal Recessive means that you would have to have inherited an abnormal gene from both your mother
and your father in order to get the disorder. So, quite commonly, you would have no family history,
as your Mum and Dad would have had only one abnormal gene each, where two genes are necessary for
the development of AR-JP. In this way, it is like Cystic Fibrosis.
It is sometimes quite difficult to treat patients with YOPD. They respond well to levodopa/carbidopa (Sinemet or Madopar),
but may develop dyskinesias within a short few years, much
earlier than those with later onset, who might develop dyskinesias only after five to ten years on Sinemet/Madopar.
If you study the brains in YOPD patients, they don't have Lewy bodies, so it's a different disorder.
Genetic studies done by a Japanese group, and other groups, localised it to Chromosome 6. Since
then, they have isolated a gene called 'Parkin' - a large gene that uses a large protein - and
found that there were huge chunks of the gene missing in these patients. They had to have huge chunks of
'Parkin' missing from the abnormal gene inherited from both Mum and Dad, in other words, they were not
able to produce an adequate amount of 'Parkin' in their brain, and developed PD.
It used to be that the age range in which people developed YOPD was up to the age of forty. That has
changed somewhat recently with the publication in 1998 of research showing that the age spectrum ranged
from between seven and fifty eight. That suggests that it might be interesting, and worth doing, to
to assess how many patients who developed PD at a younger age have this autosomal-recessive gene.
It is only a one-in-four chance that the children will get the abnormal 'Parkin' gene from both Mum and Dad.
So you may have four children, but perhaps only one gets PD, so you don't have that strong family
history which might give you a clue that it might be inherited. So it would be worthwhile
doing a study to see how common this faulty gene is, which is something that has
not been determined as yet. Then you could try to find out
what its mechanism is. Because of Ireland's limited gene pool, you could do some strong studies,
particularly in this type of work,
in identifying the patients and studying the gene.
So a lot of different genes have been isolated. I was involved in a study of an Irish family
with a different form of PD, and we did succeed in isolating the gene.
Other neurological conditions where the gene has been found include
The framework of a cell is made up of microtubules, which are held together and function
by a protein we call "tau". In one Irish-American family that I studied with others,
we identified, in
colaboration with the other research groups, mutations
in tau that resulted in the Substantia Nigra of these patients being decimated. This mutation
has been found to be another different type of PD.
There is some intriguing data
to suggest that the mitochondria may not function well in people
who have PD, but this has not been finally proven. This is where Friedreich's Ataxia starts. This is a disorder which, like Young Onset PD, is
Autosomal Recessive, so again, there is not much of a family history, but it is
inherited. The protein there gets localised to the energy aspect of the cell, called the mitrochondria.
Alpha synuclein gets localised to the cell body. It may not be being
processed correctly, and so starts to acccumulate in clumps of these Lewy bodies and bunging up the cell.
There seems to be some evidence of that.
We are not sure about what the "Parkin" gene does to protein, but it seems to have a similar
function to another protein in the cell called ubiquitin. The ubiquitin protein is known
to be a garbage disposal cell whose function is to "chew up" these proteins, but sometimes
the by-products are not "digested", and accumulate. That's one of the problems in Autosomal
Recessive Parkinson's.
To conclude, Ireland may have an important role to play in research into the
genetics of Parkinson's, particularly because of its large families.
So far, this has not really been tapped into or utilized.
Introduction
Types of Parkinsonism
The most important thing when I see patients with Parkinsonism for the first time
is to make a correct diagnosis, as the treatment varies depending on the diagnosis, and
what I may be able to tell the patient to anticipate or expect may be quite different in each case.
Regions of the Brain Affected by Parkinson's Disease
Parkinson's affects that portion of the Mid-Brain called the "Substantia Nigra". This is the
area that pumps out dopamine in order to make the brain's automatic
movement centres work. If you don't have enough dopamine, then the automatic movement centres, or "computers" -
the basal ganglia - don't work, and you end up displaying the symptoms of PD.
Etiology - What Causes Parkinson's?
Hereditary Studies
Environmental Studies
I am somewhat doubtful about these, as most of the data is now old. It was asked if it could be
due to a slow-acting virus. That hearkens back to the 1918-1919 influenza virus. About one-third of the
world's population died, but some of
those who survived developed, later on in life, Parkinsonism - a particular form of Parkinsonism
called Encephalitis Lethargica. That's the Parkinsonism that you can see in the movie
"Awakenings". The patients were confined to bed and getting progressively worse, and using
levodopa was something out of the ordinary.
A
National Brain Bank
has recently been set up in Beaumont Hospital for research into neurodegenerative disorders. Despite recent controversies, a brain serves
a very useful purpose when a patient passes away - that of confirmation of diagnosis, with the remaining portion frozen and
used for later study. So a brain bank is of critical importance in helping to advance research. 
But is it Parkinson's Disease?
In Wilson's
Disease, which can commonly present in teenagers or even in young people in their twenties, symptoms are
due to a
copper abnormality. This is a very treatable disorder. These disorders are all very rare. So the diagnosis is not always that of PD, but
the other disorders must be ruled out first. For instance, in Segawa's Disease, patients get dystonia
in early onset of PD. PD Patients can get dystonia too, but usually it's somewhat later in the disorder.
Sometimes a young person presents early in Huntington's Disease with the symptoms of PD, as distinct from
thet personality changes and chorea seen in Huntington's Disease. Therefore, all these
disorders must be considered when a patient presents with PD-like symptoms.
Young Onset PD and Genetics
Autosomal-Recessive Juvenile Parkinsonism
In Familial CJD or 'Mad Cow Disease', for instance, it can initially have some of
the symptoms of PD, but usually progresses quite rapidly. Most of these have been identified
in the last three-to-five years, so the field has changed quite dramatically.
The Framework of a Cell
A Neuron
This cell has a nucleus in the center, dendrites around the edge, and an axon leading down towards
the synapse in order to pass on instructions.
We have billions of these cells. We are now beginning to be
aware of where in the cell the problems start.
Section Two: Current Treatments |
Section Three: Starting Treatment |
Section Four: Glossary
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