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\title{Science AMA Series: Hi, I'm Jonathan Ling, a researcher that's here to
share our new breakthrough discovery for ALS (amyotrophic lateral
sclerosis)}



\author[1]{ALS-researcher }%
\author[1]{Jonathan Ling}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 08, 2026}


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\begin{abstract}
Hey reddit, Today, in the journal Science, you can find our paper which
describes the function of TDP-43, an important protein in ALS (the
disease that the ice bucket challenge raised money for) tl;dr: TDP-43
doesn't do its job in 97\% of all ALS cases. Scientists didn't really
know its function---now we do. We also show that it's something that can
be fixed! ELI5 Cells in your body are constantly reading your DNA to
make proteins. DNA is located in the nucleus of a cell. You can think of
a nucleus as a library except that instead of having books neatly lined
up on shelves, the books in a nucleus have all of their pages ripped out
and thrown around randomly. To sort through this mess, the cell has
great librarians that go around collecting all these pages, collating
them and neatly binding them together as books. These librarians then
ship these ``books'' out of the nucleus so that other workers in the
cell can do their jobs. Think of these books as instruction manuals.
TDP-43 is a very special type of librarian. TDP-43's job is to ensure
that nucleus librarians don't accidentally make a mistake and put a
random nonsense page (usually filled with gibberish) into the books that
they ship out. If one of these nonsense pages makes it into an
``instruction manual'', the workers in the cell get really confused and
mess things up. For terminology, we call these nonsense pages ``cryptic
exons''. Here's an image to help illustrate my analogy. In the brains of
ALS patients, some cells begin to get sick because TDP-43 becomes really
sticky and clumps together outside the nucleus, where it can't do its
job. See this image here. We've known about TDP-43 for nearly a decade
but never really understood what it did. Today, in our Science paper, we
actually show evidence of cryptic exons in the brain autopsies of ALS
cases, suggesting that some of our theories were right all along: TDP-43
isn't doing its job correctly in ALS. So, what does this mean for
potential therapies? Well, we took mouse stem cells and completely
deleted TDP-43 to show that without TDP-43, a cell can't survive more
than 2-3 days. However, when we genetically inserted a special protein
designed to mimic TDP-43's ``librarian'' function (i.e. prevent random
nonsense pages from entering the instruction books of the cell), these
cells came back to life and looked completely normal. In other words,
these cells had absolutely no TDP-43 inside them but were almost
completely healthy. Here's an image of those cells. If we are able to
mimic TDP-43's function in the human neurons of ALS patients, there's a
good chance that we could slow down progression of the disease! And
that's what we're putting all our efforts into right now. Quick note for
readers who are well versed in biology TDP-43's splicing repression
mechanism is actually quite interesting and hints at a model for the
evolution of exon-intron definition. I think biologists have long
wondered how the cell can recognize short 50-200bp exons that are
separated by gigantic 100kb introns. How is it that random exons don't
just pop up in the intron region by chance? Well, it seems like the cell
recruits microsatellite targeting RNA-binding proteins that act as
general splicing repressors. This is further supported by the
observation that the mechanism of cryptic exon repression is highly
conserved across species but the targets are actually 100\% different.
Furthermore, expansions or contractions of these microsatellite
``intronic splicing suppressor'' elements could represent loci for
disease risk. I think it's an exciting time for this discovery,
especially with the advent of whole genome sequencing. Anyways I mainly
wanted to do this AMA because I remember reading a lot of stories about
people complaining that the ice bucket challenge was a waste and that
scientists weren't using the money to do research, etc. I assure you
that this is absolutely false. All of your donations have been amazingly
helpful and we have been working tirelessly to find a cure. With the
amount of money that the ice bucket challenge raised, I feel that
there's a lot of hope and optimism now for real, meaningful therapies.
After all, the best medicines come from a full understanding of a
disease and without the financial stability to do high risk, high reward
research, none of this would be possible! Of course, there is always
more to be done so please consider donating to the ALS Association or
the Packard Center for ALS here at Johns Hopkins. If you're interested
in supporting the work of our lab directly, you can also do so here.
Here is a gallery of images as well That's it. I'll be back at 1 pm ET
to answer your questions, Ask Me Anything! EDIT: Thank you everyone for
all the questions! Sorry if I didn't get to you, I will check back on
the AMA later and try to respond. -Jon%
\end{abstract}%



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