5 ms·

An ALS Protein, Revealed

135 points by nabla9 5y ago

zackees 5y ago
flobosg 5y ago
> Remember, the protein-folding software works by analogy to known structures, which for the bulk of proteins can take you quite far (with ingenious software and lots of processing power). But they will not create new protein folds ex nihilo. This is only true if you take AlphaFold or RosettaFold into consideration. However, there are protein design software suites (including Rosetta, which is part of RosettaFold) able to generate de novo protein folds not found in natural proteins[1]. Furthermore, many of those models have been demonstrated, using experimental methods, to adopt the desired structure in solution. [1]: Here’s an early example - https://www.science.org/doi/10.1126/science.1089427 https://www.science.org/doi/10.1126/science.1089427
- hrgiger 5y ago
  *Downloadable [1]: https://www.researchgate.net/publication/8996963_Design_of_a_Novel_Globular_Protein_Fold_with_Atomic-Level_Accuracy https://www.researchgate.net/publication/8996963_Design_of_a...
StephenSmith 5y ago
Both of my Grandmothers died of this terrible disease (My mom's mom and my Dad's mom, obviously no relation). One died well before I was born and the other when I was only 8. It takes away your ability to communicate pretty early on, as you slowly lose access to your muscles, all while your brain remains active. The inability for one to help themselves really makes this just horrible. I often worry about the genetic implications of this. If the disease has any genetic predisposition, then I would certainly be out of luck. My mother and father are both well, approaching 60, but they would only have half of the genetic concern I do. We just don't know. The disease remains a serious mystery to us. I hope that in my lifetime, we are able to understand more about the disease, what causes it, and hopefully find a cure.
- tasty_freeze 5y ago
  > they would only have half of the genetic concern I do. It is complicated. If it is due to a flaw in one of the X or Y chromosomes, that greatly changes the calculation. Dominant/recessive categories changes the math. But ignoring all that, it seems like you have the same risk as your parents: for them, there is a 50% chance they got it from one known carrier; for you, there is a 25% change of having gotten it from each of two known carriers.
  - callesgg 5y ago
    That is assuming a very simple genetic model that is only fully valid in cases where a symptom is caused by a single gene malfunctioning by it self. Also ignoring gene to gene interactions that can have adative or worse effects.
    - tasty_freeze 5y ago
      Exactly -- like I said, it is complicated. What I said was the simplest case possible: not X/Y related, disease caused by a single gene.
- karrot-kake 5y ago
  The disease may not be genetic. Only a small percentage is. My dad has ALS and in his case is not genetic (lucky me). The disease starts and progresses in different paces for different people - my dad has it for almost 7 years and still talks and eats like before. For him, the first thing to go was his arms; now his legs are almost paralyzed as well. In his case, it probably is associated with the fact that he worked with agrochemicals his whole life, in a time when regulations and PPE where much loosier. He tells stories of taking baths of substances while his dad worked in orchards.
  - ravedave5 5y ago
    My mother in law got it from agro chemicals as well.
  - 5y ago
programmarchy 5y ago
The article mentions it’s a prion or prion-like. Kinda scary. Does our immune system not have any way to fight prions? If not then presumably vaccines wouldn’t work against them either.
- flobosg 5y ago
  > Does our immune system not have any way to fight prions? The normal and misfolded versions of a prion have the same protein sequence. This lack of differentiation allows the pathogenic form of prions to remain undetected by the immune system.
  - programmarchy 5y ago
    I understand that it’s the same sequence but the immune system doesn’t “know” about the sequence, it “knows” about the shape, no? Seems like a misfolded protein would have a different shape and receptors would bind to it differently.
    - flobosg 5y ago
      You’re right, antibodies are able to recognize shape. Several early steps of the immune response, however, are independent of conformation. For example, in order to be presented, protein antigens are usually processed and chopped into small peptides, and these may be similar between both prion variants. Additionally, prion proteins can be resistant to that sort of processing.
      - epgui 5y ago
        For more info about what this commenter is talking about: - https://en.wikipedia.org/wiki/Antigen-presenting_cell https://en.wikipedia.org/wiki/Antigen-presenting_cell - https://en.wikipedia.org/wiki/Major_histocompatibility_complex https://en.wikipedia.org/wiki/Major_histocompatibility_compl...
- dmead 5y ago
  There's a ted talk out there that supposed that people who develop als all spent time in forests/streams.
sonicggg 5y ago
Very frightening to know that we still do not have a good grasp on causes, and are probably several decades away from being able to treat it. It's really a death sentence. I would probably choose a quick way out if I were ever diagnosed.
josefrichter 5y ago
Horrible disease. It's interesting that Stephen Hawking suffered from it, yet he lived a long life.
- bobf 5y ago
  From the current research, the best conclusion I've been able to arrive at is we still don't really understand ALS. My opinion is that there may be several distinct motor neuron diseases, each with accompanying cause[s], currently grouped together in what we call ALS. There are notable differences in early vs. later onset ALS, slow vs. rapid disease progression, initial primary symptoms, genetic links vs environmental factors, etc. (I'm not a doctor or professional academic in the field, but I've studied ALS research extensively - a relative was diagnosed and died from it, suddenly, in their early 60s.) Stephen Hawking is definitely inspiring, with a few unique points - he had an early onset of the disease, slow disease progression, and extensive resources/access to the most advanced care. With mechanical ventilation, caregivers, sheer will, some luck (basically, not contracting a fatal case of pneumonia), tracheotomy and feeding tube, etc - life expectancy with ALS can certainly be extended far beyond what was once thought possible though.
  - deleted 5y ago
    [deleted]
heygood 5y ago
I remain hopeful that an ALS cure will be developed in the coming years. Knowing that there is a 50% chance my mother will get it or 25% chance that I could can fill you with a unique form of existential dread.
ilove196884 5y ago
The lab which they are talking about invented cryo em .
NaturalPhallacy 5y ago
This is what took my mother from me. Now every time I trip for no reason (one of her earliest symptoms), or have an involuntary twitch, I wonder if I'm developing symptoms. Horrible disease. It takes your ability to talk from you.
lysozyme 5y ago
The technique used here to get pictures of the folded proteins (cryo-electron microscopy, or cryo-EM) has seen steady improvements over the past couple of decades. [1] It’s analogous to room temperature light microscopy like you might have done in school, but with electrons instead of photons: >Imaging biological objects in an electron microscope is, in principle, analogous in some respects to light-microscopic imaging of cell and tissue specimens mounted on glass slides. In light microscopy, visible photons serve as the source of radiation; once they pass through the specimen, they are refracted through glass optical lenses to form an image. In electron microscopy, the radiation is electrons, emitted by a source that is housed under a high vacuum, and then accelerated down the microscope column The number of protein structures determined via cryo-EM is growing fast. Why is cryo-EM exciting for protein structure determination? The primary technique for determining protein structures is X-ray crystallography, which, as the name implies, requires you to first produce, purify, and crystallize the protein. In contrast, cryo-EM allows determination of the protein structure without having to crystallize it. In a typical cryo-EM experiment for protein structure determination, the protein molecules are imaged sparsely on a thin film, and many 2-D images are taken. These 2-D images are used to reconstruct the 3-D structure using a variety of computational techniques (including, recently, deep learning) >images of the object, each with a different orientation, have 2D Fourier transforms that correspond to sections (indicated by red arrows) through the 3D Fourier transform of the original object. Thus, once the 3D Fourier transform is built up from a collection of 2D images spanning a complete range of orientations, Fourier inversion enables recovery of the 3D structure In the analogous X-ray crystallography experiment, you have to grow crystals of your protein before imaging. The conditions that provide nice crystals are unknown and crystallization itself is sometimes completely out of the question, such as in this article where the authors are imaging a tissue sample 1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537914/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537914/

135 points by nabla9 5y ago

> Remember, the protein-folding software works by analogy to known structures, which for the bulk of proteins can take you quite far (with ingenious software and lots of processing power). But they will not create new protein folds ex nihilo. This is only true if you take AlphaFold or RosettaFold into consideration. However, there are protein design software suites (including Rosetta, which is part of RosettaFold) able to generate de novo protein folds not found in natural proteins[1]. Furthermore, many of those models have been demonstrated, using experimental methods, to adopt the desired structure in solution. [1]: Here’s an early example - https://www.science.org/doi/10.1126/science.1089427 https://www.science.org/doi/10.1126/science.1089427

hrgiger 5y ago
*Downloadable [1]: https://www.researchgate.net/publication/8996963_Design_of_a_Novel_Globular_Protein_Fold_with_Atomic-Level_Accuracy https://www.researchgate.net/publication/8996963_Design_of_a...

StephenSmith 5y ago

Both of my Grandmothers died of this terrible disease (My mom's mom and my Dad's mom, obviously no relation). One died well before I was born and the other when I was only 8. It takes away your ability to communicate pretty early on, as you slowly lose access to your muscles, all while your brain remains active. The inability for one to help themselves really makes this just horrible. I often worry about the genetic implications of this. If the disease has any genetic predisposition, then I would certainly be out of luck. My mother and father are both well, approaching 60, but they would only have half of the genetic concern I do. We just don't know. The disease remains a serious mystery to us. I hope that in my lifetime, we are able to understand more about the disease, what causes it, and hopefully find a cure.

tasty_freeze 5y ago
> they would only have half of the genetic concern I do. It is complicated. If it is due to a flaw in one of the X or Y chromosomes, that greatly changes the calculation. Dominant/recessive categories changes the math. But ignoring all that, it seems like you have the same risk as your parents: for them, there is a 50% chance they got it from one known carrier; for you, there is a 25% change of having gotten it from each of two known carriers.
- callesgg 5y ago
  That is assuming a very simple genetic model that is only fully valid in cases where a symptom is caused by a single gene malfunctioning by it self. Also ignoring gene to gene interactions that can have adative or worse effects.
  - tasty_freeze 5y ago
    Exactly -- like I said, it is complicated. What I said was the simplest case possible: not X/Y related, disease caused by a single gene.
karrot-kake 5y ago
The disease may not be genetic. Only a small percentage is. My dad has ALS and in his case is not genetic (lucky me). The disease starts and progresses in different paces for different people - my dad has it for almost 7 years and still talks and eats like before. For him, the first thing to go was his arms; now his legs are almost paralyzed as well. In his case, it probably is associated with the fact that he worked with agrochemicals his whole life, in a time when regulations and PPE where much loosier. He tells stories of taking baths of substances while his dad worked in orchards.
- ravedave5 5y ago
  My mother in law got it from agro chemicals as well.
- 5y ago

programmarchy 5y ago

The article mentions it’s a prion or prion-like. Kinda scary. Does our immune system not have any way to fight prions? If not then presumably vaccines wouldn’t work against them either.

flobosg 5y ago
> Does our immune system not have any way to fight prions? The normal and misfolded versions of a prion have the same protein sequence. This lack of differentiation allows the pathogenic form of prions to remain undetected by the immune system.
- programmarchy 5y ago
  I understand that it’s the same sequence but the immune system doesn’t “know” about the sequence, it “knows” about the shape, no? Seems like a misfolded protein would have a different shape and receptors would bind to it differently.
  - flobosg 5y ago
    You’re right, antibodies are able to recognize shape. Several early steps of the immune response, however, are independent of conformation. For example, in order to be presented, protein antigens are usually processed and chopped into small peptides, and these may be similar between both prion variants. Additionally, prion proteins can be resistant to that sort of processing.
    - epgui 5y ago
      For more info about what this commenter is talking about: - https://en.wikipedia.org/wiki/Antigen-presenting_cell https://en.wikipedia.org/wiki/Antigen-presenting_cell - https://en.wikipedia.org/wiki/Major_histocompatibility_complex https://en.wikipedia.org/wiki/Major_histocompatibility_compl...
dmead 5y ago
There's a ted talk out there that supposed that people who develop als all spent time in forests/streams.

sonicggg 5y ago

Very frightening to know that we still do not have a good grasp on causes, and are probably several decades away from being able to treat it. It's really a death sentence. I would probably choose a quick way out if I were ever diagnosed.

josefrichter 5y ago

Horrible disease. It's interesting that Stephen Hawking suffered from it, yet he lived a long life.

bobf 5y ago
From the current research, the best conclusion I've been able to arrive at is we still don't really understand ALS. My opinion is that there may be several distinct motor neuron diseases, each with accompanying cause[s], currently grouped together in what we call ALS. There are notable differences in early vs. later onset ALS, slow vs. rapid disease progression, initial primary symptoms, genetic links vs environmental factors, etc. (I'm not a doctor or professional academic in the field, but I've studied ALS research extensively - a relative was diagnosed and died from it, suddenly, in their early 60s.) Stephen Hawking is definitely inspiring, with a few unique points - he had an early onset of the disease, slow disease progression, and extensive resources/access to the most advanced care. With mechanical ventilation, caregivers, sheer will, some luck (basically, not contracting a fatal case of pneumonia), tracheotomy and feeding tube, etc - life expectancy with ALS can certainly be extended far beyond what was once thought possible though.
- deleted 5y ago
  [deleted]

heygood 5y ago

I remain hopeful that an ALS cure will be developed in the coming years. Knowing that there is a 50% chance my mother will get it or 25% chance that I could can fill you with a unique form of existential dread.

ilove196884 5y ago

The lab which they are talking about invented cryo em .

NaturalPhallacy 5y ago

This is what took my mother from me. Now every time I trip for no reason (one of her earliest symptoms), or have an involuntary twitch, I wonder if I'm developing symptoms. Horrible disease. It takes your ability to talk from you.

lysozyme 5y ago

The technique used here to get pictures of the folded proteins (cryo-electron microscopy, or cryo-EM) has seen steady improvements over the past couple of decades. [1] It’s analogous to room temperature light microscopy like you might have done in school, but with electrons instead of photons: >Imaging biological objects in an electron microscope is, in principle, analogous in some respects to light-microscopic imaging of cell and tissue specimens mounted on glass slides. In light microscopy, visible photons serve as the source of radiation; once they pass through the specimen, they are refracted through glass optical lenses to form an image. In electron microscopy, the radiation is electrons, emitted by a source that is housed under a high vacuum, and then accelerated down the microscope column The number of protein structures determined via cryo-EM is growing fast. Why is cryo-EM exciting for protein structure determination? The primary technique for determining protein structures is X-ray crystallography, which, as the name implies, requires you to first produce, purify, and crystallize the protein. In contrast, cryo-EM allows determination of the protein structure without having to crystallize it. In a typical cryo-EM experiment for protein structure determination, the protein molecules are imaged sparsely on a thin film, and many 2-D images are taken. These 2-D images are used to reconstruct the 3-D structure using a variety of computational techniques (including, recently, deep learning) >images of the object, each with a different orientation, have 2D Fourier transforms that correspond to sections (indicated by red arrows) through the 3D Fourier transform of the original object. Thus, once the 3D Fourier transform is built up from a collection of 2D images spanning a complete range of orientations, Fourier inversion enables recovery of the 3D structure In the analogous X-ray crystallography experiment, you have to grow crystals of your protein before imaging. The conditions that provide nice crystals are unknown and crystallization itself is sometimes completely out of the question, such as in this article where the authors are imaging a tissue sample 1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537914/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537914/