Parkinson’s Disease and the Silver Tsunami | Valina Dawson, Ph.D.


>>So today I’d like to talk to you about Parkinson’s disease, and
the problem that it’s going to face our society and our
community in the coming years. The term, the Silver Tsunami
was not coined by me. It’s one that’s been in
the medical literature for the last couple of
years since physicians and caregivers are becoming
more and more concerned that how we are going to deal with
our rapidly aging population and the various diseases that
they’re going to be developing that will need treatment and care. There we go. So Parkinson’s disease
is the second most common neuro degenerative disease
so far in the world. It’s only behind Alzheimer’s disease. It’s estimated that there
are over 1.5 million people who suffer from the disease today. It’s thought with the
aging of the Baby Boomers that this will double or
triple in the next 20 years. Right now, it’s costing us
over 14 billion dollars a year in caregiving in medical
care for these patients. So of course this is also
going to double or triple. This is a chronic, neuro
degenerative disease. There is no treatment. There is no cure. There is no way to stop the disease. What we do have are some
palliative therapies. We treat the symptoms. We can give some drugs
that we replace dopamine, which is the neurotransmitter
that’s being lost. You heard about
neurotransmitters from Rick and earlier from the other
sparks or you can drop in an electrode into particular
parts of the brain and try and reestablish a circuit and that will help with
some of the motor deficits. But none of these
treatments stop the disease. So at some point, these
treatments fail because the disease continues to progress. Now there’s some features
about this disease that people don’t quite know about and some of our scientists
don’t know about this, so they’re not modeling the
disease as well as they could. The idea is that mostly
it’s men who get the disease and that’s not true. We just have some people
here who have suffered or died from Parkinson’s. It roughly is more men than women, but both genders can get the disease. It’s not specific for
any kind of nationality or ethnic background. It is your risk factor for
developing the disease is aging and so it’s more common to
see the disease in people over the age of 60. However, this individual
that’s recently diagnosed that’s a two year old boy. This individual was diagnosed at 11. He is now 20. He suffered from unknown
neurologic complications for six to seven years before
physicians finally realized that what he had was
actually Parkinson’s disease. So this is a disorder
that can reach across all ages and all people. People tend to think
of Parkinson’s disease as this movement disorder, this shaking. This is really when at the
end stage of the disease that you see these motor deficits. It really starts very early
on and we think it starts now in the gut. So some of the first
complications is the loss of the myenteric plexus which is the brain for your stomach and your GI system. This becomes dysfunctional. Patients have a lot of
synuclein load in their gut and they get constipation. As the disease progresses, it involves the autonomic nervous system. Patients will then have
problems with heart rate variability and other peripheral anatomic nervous system problems. As it moves into the brain, both the motor and non
motor parts of the brain are affected. There’s a very stereotypic sleep disorder. There is also anxiety and depression, which are very common Parkinson’s patients and very debilitating. They will eventually get some hyperosmia as the olfactory bulb degenerates, this impairs their ability
to eat and enjoy food and then as the cortex becomes involved, they become demented. 30% of patients when they
die are fully demented. They require 24 hour care
for daily tasks of living. It is estimated that 80%
of Parkinson’s patients have anywhere from mild
cognitive impairment to mild dementia. So the dementia is also
very common part or feature of the disease. So when trying to study the disease, you want to be able to study all aspects. So the way this disease
happens or the hallmark pathologic features of the disease, is this protein synuclein. Normally, it’s kind of a floppy protein. Not very structurally complex, becomes for whatever reason misfolded. And it forms these fibrils. We don’t know why this misfolding occurs but it is the feature
of PD as well as other synucleinopathies, which are
dementia with Lewy bodies and multiple systems atrophy. These fibrils then collect and they form what are called the Lewy bodies and these are the hallmark
features that the pathologists will use on post-mortem
examination to make the final conclusive diagnosis
of Parkinson’s disease. But we think that it is
these pathologic fibrils that are causing the disease and what we think is occurring is that these fibrils they take the
normal synuclein in a cell, you just need a few misfolded
alpha-synuclein fibrils. And they cause the normal
synuclein to misfold, so you get this amplification effect. Then these fibrils get down
into the nerve terminals where they’re secreted
and they’re picked up by the neighboring
neuron that’s next door. So recently we discovered
and published in science that the protein that picks
these fibrils up is LAG3. It’s normally involved
in the immune system. It only recognizes these fibrils. It does not recognize normal synuclein. And if you knock out LAG3, you can completely block the
transmission of synuclein. You can block the progression
of Parkinson’s disease. So we are fairly
confident that this is how the disease is progressing. We think it starts in
the lower systems in the myenteric plexus, and then
moves from neuron to neuron so where the synapses occur,
that’s where the fibrils move. So we have spent decades
studying Parkinson’s disease and defining better and
better model systems. This is our approach. We start with the patient. Some patients have genetic mutations. These are very rare. It’s only 10-15% of the total population. We get post-mortem tissue. We get biologic samples and we use these to test hypothesis that we’re developing
in our animal models. So we have a sporadic model, with these preformed
fibrils, toxic synuclein, engineered models and
then we also have cultures derived from stem cell
technologies of the brain region so we can reproduce the brain
regions and the cell types we want to study. We get an idea using genomics,
proteomics, cell biology, of what the signaling,
pathologic signaling pathway is. We test that. And then we try and find new therapeutics and new targets and ways to block this. When we do find a new drug, we don’t just go moving
into clinic immediately. We run it through the
whole battery of our models to make sure that we
haven’t fooled ourselves and that truly is a good target. This is what we’ve found over the decades. We have this alpha synuclein aggregation. We don’t know why that starts, but once it does and it gets into a cell, it causes some kind of
mitochondrial dysfunction which then activates this molecule C-Abl. Parkin is a gene that gets inactivated in familial PD, but is
also inactivated always in sporadic PD. And Parkin has two targets. One is this molecule PARIS which regulates the ability of mitochondria
to restore themselves. So when PARIS is
over-expressed mitochondria cannot renew themselves and
they become dysfunctional. It also promotes this
protein which is involved in protein synthesis,
moves out of the cytosol into the nucleus, where it
activates this molecule PARP, and that sets in motion
the cell death process. In addition to what’s
going on in the neurons, this aggregated synuclein
activates microglia, and it causes normal
astrocytes, which you need in your brain, they provide
very healthy benefits to the cells that they surround. They turn them in from A2 happy astrocytes to these A1 astrocytes that
go around and kill neurons. So if you want to protect the brain, the reason that you had to
block cell death in the neurons, but you also had to block
the conversion of these astrocytes that didn’t have
this bad inflammatory response. This happens also in the
autosomal recessive diseases. These models have been very
handy in developing this. And so what we’ve done,
we’ve developed a number of drugs that are now moving
through different stages into the clinic. So knowing what these targets are, we have C-Abl inhibitors. Two companies are going into
clinical trial this year. Michael J. Fox is also
doing a negative study. We have inhibitors of
microglial activation. That study is going into clinical trial. We just finished our funding
that will be starting at the end of the year. We are working on PARP
inhibitors and PARIS inhibitors as well as MITH inhibitors,
and those are in various stages of development, but these we anticipate at
least for the PARIS inhibitors that in a year and half to two years, we will also be going
into clinical studies. So in the next year,
you’ll be seeing hopefully you’ll be hearing from us
about our clinical trials, as well as some of the basic
science of what we’re trying to do to understand better
how synuclein misfolds and causes this Freon like effect and how that might be
also used as a biomarker and additionally we have some
good work with neuro imaging so that we can follow the
disease as it progresses or hopefully as we prevent
it from progressing. So thank you very much. (audience applauding)>>Carol: I’m Carol Pearson. I’m with the Voice of America. And I interviewed a doctor who specialized in treating Parkinson’s. He said that he felt that
there was something related to diet, his brother had Parkinson’s and he said that after
that he was very particular about the type of food
he ate and would only buy organic fruits and vegetables,
because he was concerned that there might be
something in non-organic fruits and vegetables that
could promote Parkinson’s. Do you have any information on that?>>So certainly there are
pesticides that are thought to provoke Parkinson’s disease
and have been used in the past to do an intoxication
model in lower organisms, mice, worms, and fish. The role of the microbiome
is a new and emerging area. We know that the microbiome
regulates innate immunity and innate immunity, also
regulates the progression of Parkinson’s, Alzheimer’s, stroke, the severity of the diseases. How that all is inter-connected
is still a work in progress. These are new areas that
are just been recognized to be important. But I think you’ll see a lot
coming out in the next few years about how those, they factor in. So diet would of course
regulate microbiome which then may regulate could
regulate the progression of the disease. He also may just be
trying to avoid some of Monsanto’s drugs, which we
do know can help accelerate things if they don’t actually trigger.>>Carol: If I could
ask one other question. What about some other diseases
that have similar symptoms, I’m thinking about
progressive supranuclear palsy for example, do we know, I
mean it’s not Parkinson’s, but do we know anything
more about these diseases and do they proceed in any
kind of similar fashion.>>So many of these
neurodegenerative diseases have at their core misfolded proteins,
which then seem to seed in a stereotypic pattern,
specific for that type of disease. I don’t know specifically
about supranuclear palsy. We are doing similar studies
in our Alzheimer’s model and we are working with the
folks at Hopkins to look at multiple sclerosis. I think that this will be a common theme and then it’ll just be which
kind of pyrenoids these are. The synuclein that misfolds
in Parkinson’s disease will give mice Parkinson’s
disease but not MSA. But if we take the new synuclein misfolded in the MSA patient, it
will give the mice MSA. So theoretically same protein, but there is some biophysical
difference between them that causes a different disease. And that’s really where
we are right now is trying to understand those aspects so that we have a better idea of how to model and then treat the diseases.>>Carol: Thank you.>>Participant: You had
mentioned the roundup glyphosate and the Shikimate pathway
has been demonstrated to be adversely affected by glyphosate. I was curious because ALS,
Parkinson’s, Alzheimer’s, I can go on and on,
they’re all characterized by this abnormal aggregation or folding and are we looking upstream
to any of those to try to find something that could
prevent us from this Silver Tsunami or whatever?>>Right that’s a very good question. Jay Parish at Johns Hopkins
working with our group. He is a GI doctor. We’ve got some models set up
using our stem cell technology to try and find out what
actually would cause synuclein to fold. Would it be just an infectious agent? Could some of these toxins
that we have in our environment naturally at very high
levels more than we ever thought we would, could
that be a promoting cause? We are just at the early stages of this. And applied for grant funding for it. I hope we have answers quickly but taking on Monsanto
is a daunting thing, so we will try that.>>Jennie: Hi Jennie Cook, freelance. I’m wondering about the
stage at which the disease is generally diagnosed, and
if it’s possible at this stage to do diagnosis based on
gut acitivity or inactivity.>>So typically it’s diagnosed
when the patient comes in because they have a tremor. Up to this point, they’ve had
symptoms that could belong to a host of other diseases. There are several things
that are advancing this, that it could be a pre-diagnosis. One is that when you get
your happy 50th birthday colonoscopy that they might
take a little deeper incision and look for synuclein aggregation because it’s become clear that early. The sleep disorder that I
mentioned, a number of these patients have gone into the
sleep labs to be studied and try to be helped for this. And they’ve been following up over time and of the patients that were
enrolled within three years 50% have converted to Parkinson’s disease. They’re following the rest
and anticipating within two all of them will have PD. And so this sleep
disorder maybe a very good early diagnostic predictor
of who’s going to get Parkinson’s disease and that
was published in the Lancet last year, not by us, unfortunately.>>Valina thank you very much.>>Okay I’ll come get you.

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