[HN Gopher] An ALS Protein, Revealed
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An ALS Protein, Revealed
Author : nabla9
Score : 65 points
Date : 2022-03-04 18:51 UTC (4 hours ago)
(HTM) web link (www.science.org)
(TXT) w3m dump (www.science.org)
| heygood wrote:
| 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.
| programmarchy wrote:
| 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 wrote:
| > 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 wrote:
| 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 wrote:
| 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 wrote:
| 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...
| dmead wrote:
| There's a ted talk out there that supposed that people who
| develop als all spent time in forests/streams.
| rindalir wrote:
| 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/
| manmal wrote:
| 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)
| CoastalCoder wrote:
| 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.
| hunterb123 wrote:
| 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.
| deltaonefour wrote:
| 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.
| alfon wrote:
| "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 has been either
| with IV antibiotics, or years of Mercury chelation
| alfon wrote:
| https://www.youtube.com/watch?v=UY9FdULDV6M
|
| https://www.lymeneteurope.org/forum/viewtopic.php?t=3647&fb
| c...
|
| Who knows..
| flobosg wrote:
| > 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
| StephenSmith wrote:
| 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.
| karrot-kake wrote:
| 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.
| bobf wrote:
| 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.
| ravedave5 wrote:
| My mother in law got it from agro chemicals as well.
| tasty_freeze wrote:
| > 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 wrote:
| 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.
| throwawayboise wrote:
| 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.
| josefrichter wrote:
| Horrible disease. It's interesting that Stephen Hawking suffered
| from it, yet he lived a long life.
| bobf wrote:
| 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]
| sonicggg wrote:
| 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.
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