6.5 CAG repeats in HD

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Del curso dictado por Peking University

Advanced Neurobiology II

58 calificaciones

Peking University

Advanced Neurobiology II

58 calificaciones

Hello everyone! Welcome to advanced neurobiology! Neuroscience is a wonderful branch of science on how our brain perceives the external world, how our brain thinks, how our brain responds to the outside of the world, and how during disease or aging the neuronal connections deteriorate. We’re trying to understand the molecular, cellular nature and the circuitry arrangement of how nervous system works. Through this course, you'll have a comprehensive understanding of basic neuroanatomy, electral signal transduction, movement and several diseases in the nervous system. This advanced neurobiology course is composed of 2 parts (Advanced neurobiology I and Advanced neurobiology Il). They are related to each other on the content but not on scoring or certification, so you can choose either or both. It’s recommended that you take them sequentially and it’s great if you’ve already acquired a basic understanding of biology. Thank you for joining us!

De la lección

Movement and movement disorders II

6.1 The dopamine system17:11

6.2 Basal ganglia and its two pathways14:47

6.3 HD deficits in basal ganglia4:21

6.4 Anatomical deficits of HD5:36

6.5 CAG repeats in HD8:21

6.6 Are aggregations proper drug targets?8:57

6.7 Symptoms of PD6:31

6.8 Genes of familial PD13:33

6.9 Interventions of PD14:00

Conoce a los instructores

Chenjian Li
Professor
School of Life Sciences
Donggen Luo
Research Fellow
School of Life Sciences
Yan Zhang
Professor
School of Life Sciences, Peking University

Okay, shall we?

Now, I mentioned that in the disease gene called Huntington.

There is a CAG repeat.

Anyway, in normal and diseased patients, the difference is CAG length.

In normal human beings, we have 17,18 no more than 35 and

between 35 and 40 it's really a disease prone area but

above 40 clearly a person will have disease.

Here is a plot take from one of the early research papers.

You can see that the X axis, that's the age.

The Y axis, that's the age of onset.

All right, so by looking at this figure, what can you find?

Describe that for me please.

Very good.

The longer the CAG repeats are, the earlier you get the disease.

So the disease is more severe, right?

Okay, now below 40, you may not get the disease.

If you go to 69,86, three years old, you get the disease.

So there is a clear correlation between the age of onset and the CAG length.

The longer it is the worse it is.

Now, what else?

What else can you observe from looking at this figure?

If you look at the arrow bar, right, on the left hand side,

the arrow bar is like this.

The longer the CAG is,

the more certain that this person is going to get disease at certain age.

Very good observation.

>> [INAUDIBLE] >> That's not true, that's not true.

We have enough sample now.

Good point, but that's not true, okay, good guess.

So it is.

It has, what does that mean?

What does a big arrow bar at 40, 42 what does it mean?

Can you go on?

What does it mean to you?

It means the shorter the length is, the uncertainty of whether

you have the disease, or how old you will get the disease.

It varies a lot, right?

It means also the toxicity of that molecule,

whatever it is, is a little bit less than optimal.

It's less severe, right?

Remember, if you have 35 or 30 you don't get the disease, that's the thing.

The longer the CAG is, the more toxic the protein is.

And therefore somehow it eliminated all the other factors that become so dominant.

As the says, in these ones,

maybe the environment and other factor or

factors, they came into play.

Whereas if you a very long CAG repeat, forget about all the others.

You are going to have a dominant, dominant effect of that disease protein.

Very good observation.

Now, I want to mention, the Huntington's disease, the Huntington

with expended CAG repeat, is a representative of a group of diseases.

They are called the trinucleotide repeat disorders.

I'm listing here, this is not the full list of

diseases but some of the main diseases.

For example, Fragile X, DM, SCA1,

2, 3, 4, all the way down.

So, these are all movement disorders.

And interestingly, sorry, not all of them, Fragile X is a mental retardation disease.

The mutated gene, they all have extended trinucleotide,

some are CAG, some are CTG, so on and so forth.

Okay, so this is a group of disease.

This is showing where the mutations are.

Huntington is a huge protein and the axon1 contains that polyglutamine.

CAG encodes PolyQ, okay?

Here I'm showing the different trinucleotide disease.

When they have this stage of onset plot,

very similar to the one we saw a minute ago, these are different diseases.

You can observe that all of them obey the rule

that the longer the expansion is, the more severe the disease is.

You have earlier onset, right?

You can also see the slope.

Some are very sharp, the other one are much more shallow.

That indicates the CAG repeats length's contribution, to how bad

the mutation is, it's different in the different protein context.

For example, in the shallow one, you have a wide range of changing that protein,

the sequence from a few over length to very long.

Whereas in some of the sharp ones, you only need to change just

a few CAG repeat, you get a disease.

That's the biological meaning.

Structurally, even today, even today

we don't have a great explanation why that is.

Vaguely we know can express that in a vague language, aha!

In different protein context the expansion, PolyQ, glutamine,

glutamine, glutamine is going to change the overall structure.

So that has become toxic, but that's a very vague language, right?

We don't know exactly in terms of structure.

If you have 35 versus 40, what changed?

What changed the Huntington from a totally normal protein,

suddenly becomes a highly toxic protein?

And if it longer CAG, why it's even more toxic?

By adding every 510 of CAG, the disease becomes much more severe.

And why is that?

So structural biology wise, people tried but we have not figured out.

Among the people who tried this, I met Max Perutz.

Does everybody know Max Perutz.

Max Perutz is a Nobel Laureate.

He got his Nobel for the work that his group solved hemoglobin structure, okay.

He tried it, and lots of people tried.

But this protein is very hard to grow crystals because it's sticky.

It precipitates.

To do crystallography, the first thing you need to do is the protein soluble.

And you allow it to grow crystals, right?

But this protein, it's just precipitates out.

Doesn't work.

So far, if any of you is interested in structural biology,

Somehow we should solve that structure one way or the other, and

then people have not figure it out how to do it.

Maybe, I don't know and some new way of doing things can help us

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