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5.2.3 Why do we care so much about the 10% genetic forms of neurological diseases?
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De la lección
Movement and movement disorders I
Impartido por:
Chenjian Li
Professor
Donggen Luo
Research Fellow
Yan Zhang
Professor
If we zoom in, we are not talking about cardiovascular diseases,
we are not talking about endocrine diseases, and so forth.
Metabolic diseases.
Let's focus on Neurological diseases.
In the category of neurological diseases, overall,
there's about 10% of those cases, are familial.
Means they're genetic.
About 10%.
Although some of the diseases, are much stronger.
Other ones are totally sporadic.
Sporadic means [FOREIGN], or old fashioned.
That only means it seems there's no clear family inheritance, okay.
But the genetic form, also called familiar cases,
are clearly those that who do have family inheritance, right.
It's about 10% of the cases.
My next questions to you is, well it seems, it's like a minority.
It's a minority.
Why we care about them so much?
Why?
Shouldn't we put our efforts in the other 90%?
There are much more relevant in public health issues, right?
Hopefully, from studying the 10%,
if we discovered the disease mechanisms, if we do,
maybe they are the same mechanism the other 90% are also using.
Well, that seems quite iffy.
[FOREIGN].
How do we know?
Is this, how do you know the other 90%,
they use the same mechanism as the 10%?
The fact that 90% they do not have limitation,
but they end up with the same disease, it could go either way, right?
They could go from a very different separate pathway.
Or, although there's no mutations, they still use the same
mechanism to proceed, to have obtain the disease.
So there are two possibilities.
At this point, we don't know.
We still don't know yet, but we hope
that some of the disease mechanisms are shared, okay.
Are there examples?
It's a wild guess.
It's our wishful thinking.
People could accuse us say, hey, you guys, geneticists,
you always claim that what you study is great and
it will have greater impact later on, just trust me.
Well, how do we know?
Maybe you guys are all thinking in the wrong direction.
Are there examples that some of the familial form,
disease form mechanisms are actually used in sporadic forms.
Are there?
That's a hard question.
That breast cancer gene, you can mutate that, and
of course, it's a very strong mutation, it will cause cancer.
However, if a guy, a woman, sorry,
doesn't inherit a mutated gene, let's say to start with, her gene is fine.
However, in the long life span, at some point
some of the cells obtained a mutation later on.
That is the same mechanism, right.
So if you look at the case, it may not be inherited But
it still, it hinges on the same mechanism.
Even the same gene.
That happens all the time.
That's true for prostrate cancer, for lot of cancers.
So in cancer field, it is very well known, okay?
In neurological diseases, we can say that some,
at least of the diseased cases are like that.
For example Alpha-synuclein is one of the one of the disease genes
we will discuss in the context of Parkinson's disease.
Alpha-synuclein, it's very interesting.
A patient May have Alpha-synuclein mutations,
in that case, it will be a very clear genetic familial case.
However, it doesn't have to be like that.
You can have a personal duplication with with the wild type of synuclein.
Still gives you the same disease.
Or even step back more, for people who do not have chromosomal duplication,
or people who do not have mutations either.
If the expression of Alpha-synuclein
is increased, still people suspect that's one of the reasons
that these people develop Parkinson's disease.
So, the gene can be regulated in many ways.
Not only mutations on themselves, but also the regulation of these guys, right?
In our signalling pathways the most famous one's, let's say MAP kinase pathway,
AKT and so on and so forth, PI 3-kinase,
many of these points can be regulated in many, many ways.
And sometimes the regulation is off the target.
And there you go, you have a disease.
So that is one of the reasons.
Another practical reason, it's both
from theory and from practical concern.
Another practical reason we focus so much on the genetic form,
is really a practical one because if you look at the sporadic
[FOREIGN], you just don't know where to start, right?
Let's say ten people come to you and say, hey sorry I have Alzheimer's disease.
Then you say hm, I know you are suffering,
I know the symptoms, but where do I start?
It 's really, really hard, right?
We are facing a complex problem.
Therefore, for those complex issues, those genetic form of the disease,
it provides an entry point.
[FOREIGN] It's very simple.
There is a gene on the chromosome somewhere,
and that gene must have a mutation either in the exons or
in the internal external junctions or even in its promoters, whatever.
But somewhere there is a mutation that somehow disrupts that gene,
whether it is the splicing variants or it's a poor mutation, or a truncation or
the gene is not expressed because there is a mutation in the promoter.
Whatever it is.
So you know there is a gene, and you can quickly
grasp that gene and say, aha, that is my entry point.
At least I have the gene.
And starting from there, you say what does this gene do?
What are it's adaptors?
Interacting proteins.
And in which pathway does this gene product work?
If there is a mutation, how is this pathway changed?
So there is a handle.
[FOREIGN] Okay, and to tell a joke if a student
comes to me and say, hey Professor Lee,
I have discovered how people die.
And I say, really?
That's a big discovery.
Then the student says, they die of hypothermia.
[FOREIGN] I ask, why is that?
And a student says, you know what,
I went to the morgue [FOREIGN] and measured every one of them.
Guess what, they're all four degrees.
Then Professor Lee says, how many have you done?
He said four.
N equals four is not enough, try 30.
So, the poor student went back and measured 30 of them, and
sure enough, they're all four degrees.
Then the student came back to me and said n equals 30,
and the standard deviation's really small.
I said, okay.
But still, it could be sampling bias
because you're looking at the [FOREIGN] morgue at Pikayo hospital.
What if you go to other hospitals?
Go to Chin Hao University Morgue.
Sorry, Chin Hao University doesn't have a morgue.
Let's try something else.
So the poor student went there, measured again.
So the n equals a lot and different sampling sites and they all the same.
It's like, all right.
But if we agree at all, that the student conclusion it's
not relevant to the disease cause, right.
It's a consequence.
It's something that just happened together with observation, but there is no logic,
cause effect in disease study.
This is one thing I want to remind you.
There are a lot of observations that came together.
Seems like it's always accompanying the disease, but
they are not cause effect relationships.
Be very, very careful.
I will talk about two examples later today, and the next time.
Okay, so, genetic ones,
it let us avoid that problem.
When you look at a patient, there's so many things that changed.
You really don't know what are the causes, what are the consequences,
and what are just compensatory, not even related.
You don't know.
The genetic form of the mutations, it lets you really,
really zoom in on the target right away.
Here's a gene, if it is mutated, you have it.
So, that's the importance of focusing on genetic forms, from the beginning.
Later on, people do expend.
We've never forgotten those poor patients, that belong to the other 90%.
We never forget them.
However, if you wanted to research,
it's probably much better to start with the genetic forms.
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