An ALS Protein, Revealed | Hacker News Reader

An ALS Protein, Revealed

science.org

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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.

> 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.

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.

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.

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.

My mother in law got it from agro chemicals as well.

I don't know what the interest or accessibility of edaravone (Radicava) treatment might be for your dad, but I'd be happy to share my experience with you by email if that is useful - my address is on my HN user page.

Not to be offensive, but is ALS his confirmed diagnosis? I have two family members who were diagnosed with different rare muscle-wasting diseases and have lost most of their arm and leg function over the past decade. Eating/breathing unaffected. They both lived on farms so we’ve always suspected there was a link.

Was reading this article and this comment came to my mind.

https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC4832962/

"Organophosphate poisoning is highly lethal as organophosphates, which are commonly found in insecticides and nerve agents, cause irreversible phosphorylation and inactivation of acetylcholinesterase (AChE), leading to neuromuscular disorders via accumulation of acetylcholine in the body."

My mother had it. There is no family history that we know of. At the time we were told it may be genetic, but it also may appear spontaneously.

It affects people differently. For some it strikes the feet and legs first, for some the arms and neck. Some people like Stephen Hawking live with it for years, some only survive a year or two after diagnosis.

It's rare, so diagnosis is often preceeded by wrong guesses at more common explanations for the symptoms. There is no test for it; it's basically diagnosed by ruling out everything else.

> 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

*Downloadable [1]: https://www.researchgate.net/publication/8996963_Design_of_a...

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.

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.

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.

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

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.

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/

The lab which they are talking about invented cryo em .

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.

> 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.

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.

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.

For more info about what this commenter is talking about:

- https://en.wikipedia.org/wiki/Antigen-presenting_cell

- https://en.wikipedia.org/wiki/Major_histocompatibility_compl...

There's a ted talk out there that supposed that people who develop als all spent time in forests/streams.

Weirdly, professional soccer players are disproportionately affected, while eg road cyclists are not: https://pubmed.ncbi.nlm.nih.gov/19267274/

Football players also have a 4x increased risk: https://tulsaworld.com/lifestyles/ask-the-doctor-pro-footbal...

But basketball players don’t - go figure.

Stephen Hawkins spent ca 1000h on boats during his college years (interesting since you mentioned that streams might bear some trigger)

The commonality between those effected may be the causative factor. If that same commonality is missing from those less effected it's even more supporting evidence.

In the set you presented. The only people who have increased risk of ALS are those that play sports on grass fields. Maybe that's the key? Grass.

"Ticks love to be in moist, low grass, so a lot of games, whether it's football, baseball, tend to happen in the morning. There may be dew on the grass and that's where a lot of ticks survive and hang out," Nesheiwat said.

https://www.cbsnews.com/newyork/news/ticks-lyme-disease-cdc-...

Lots of anecdotal evidence of ALS developing after tick bites, or more concretely infection with Borrelia Burgdorferi.

Probably a genetic component, and other enviromental factors are also involved, but the only dramatic reversals of MND I have seen documented (or heard about) have been either with IV antibiotics [1][3], or years of Mercury chelation [2]

[1] https://invisibledisabilities.org/award-recipients/2011award...

[3] https://pubmed.ncbi.nlm.nih.gov/17212618/

[2] https://www.researchgate.net/publication/317849075_Healing_o...

In the recent book "Chronic" by Dr. Stephen Philips, he's frustrated since he can only treat successfully (outcome similar to Dr. Martz), with antibiotics, about 15% of his ALS-like patients. Considering how uniformly fatal ALS diagnosis is otherwise, even considering how skewed of a sample he might get (patients that already know they are Lyme positive or suspect it), still find it astonishing.

Thanks for those links! Re antibiotics, do those end up in the spinal fluid and brain in „useful“ amounts?

Depends on the antibiotic. I believe their molecular mass has to be lower than around 500 Da for them to reliably cross the blood brain barrier. It also depend whether meningeal inflammation is present or not

I wonder if it correlates with head trauma? Soccer players head the ball, and American football players famously get lots of concussions. But I assume not basketball players or bikers.

I believe the eyes are a vector for prion diseases, at least some.

Possibly infection when being looked at for a head injury, but I assume they take decent precautions.

Another user proposed grass was the commonality between those sports, in that case grass/dirt entering the eyes?

For forest/streams, possibly water/dirt entering the eyes?

Doesn't really narrow much down though, avoid all dirt, grass, and water.

I‘m not sure I‘m buying the prion theory. Shouldn’t numbers decrease as people go outside ever less often? Prevalence of ALS seems to be increasing though: https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC6735526/

I think the Borrelia Burgdorfferi hypothesis would fit better, with Lyme disease numbers climbing in recent decades.

Yes, naively the connection looks like head impacts. The high rate of concussions in soccer is not widely appreciated, despite being over half the rate of American football (about which a lot more has been written).

https://storelli.com/blogs/the-storelli-blog/soccer-concussi....

https://journals.lww.com/cjsportsmed/Abstract/2001/10000/Con...

From the first link, here is the ranking of concussion rate:

1. Rugby (4.18/1,000 AE) 2. Ice hockey (1.20/1,000 AE) 3. American football (0.53/1,000 AE) 4. Lacrosse (0.24/1,000 AE) 5. Soccer (0.23/1,000 AE) 6. Wrestling (0.17/1,000 AE) 7. Basketball (0.13/1,000 AE) 8. Softball & field hockey (0.10/1,000 AE) 9. Baseball (0.016/1,000 AE) 10. Cheerleading (0.07/1,000 AE) 11. Volleyball (0.03/1,000 AE)

> Athletic Exposure (AE) is defined as one athlete participating in one game or practice.

Football and soccer players both. I'm pinging on agro chemicals--from the mentions earlier. I have to assume all natural fields are heavily treated (herbacide and insecticide) and that players spend or have spent their early career on natural fields. All of these chemicals are derived from "nerve agents" that mess with proteins in the central nervous system...or so it is my understanding.

And yet Lou Gehrig played baseball.

https://www.youtube.com/watch?v=UY9FdULDV6M

https://www.lymeneteurope.org/forum/viewtopic.php?t=3647&fbc...

Who knows..

Cause and effect may be reversed... Maybe in the very early stages of ALS, motor coordination skills are worse, making one not be as good a footballer, so you decide to take up a career as an accountant instead, who cycles at the weekends.

True, but that should affect basket players too, who don’t seem to be specifically predisposed to ALS.

That would be ... scary for me. The closest I could find was some limited evidence of an association between cyanobacteria blooms and odds of ALS in the surround population: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727154/

Can you provide a link? I’m having trouble finding it.

I believe this is it. here ya go

https://www.youtube.com/watch?v=7jWi6WQQ9wo

We got heat-shock proteins, they can be activated by IR light or substances such as sulforaphane. Genetically modified mice, with no heat-shock proteins, die faster when infected with certain prions.

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