>> 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.