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Huntington’s and Other Repeat Disorders: DNA, Not Protein?

As many will know, there is a whole set of what are termed “polyglutamine repeat disorders“, which themselves are a large part of a bigger set of trinucleotide repeat disorders. Huntington’s disease is a well-known one: the gene (HTT) for the huntingtin protein ends up with a series of CAG nucleotide repeats, which after translation to protein gives it a long set of glutamine residues. It’s been known for a long time that the severity of the disease seems to track with the number of glutamine residues: if there are fewer than 35 in a row, a person will be totally asymptomatic, with fewer than 28 being considered completely normal. 36 to 40 repeats takes a patient into a variable zone where the disease will show effects, but the age of onset and their severity will vary.  And greater than 40 is full-blown Huntington’s.

The way these form seems to be slippage during DNA copying or repair, through several mechanisms. There are many interesting and suggestive features to all these diseases: for one thing, you don’t see “dinucleotide repeat” syndromes, probably because that messes up the reading frame. Trinucleotide repeats form all sorts of loops and diversions in DNA, but it’s at least still (marginally) functional. Meanwhile, CAG is apparently the most common of the repeats, and the polyglutamines that result are thought to be likely to aggregate (leading to disease pathology). It seems that most of the repeat disorders, though, CAG or not, have approximately that 35-repeat threshold for trouble. But there’s a separate category of much larger repeats, this time showing up outside protein-coding regions, that are also associated with things like Friedrich’s ataxia. But in most all of these, the phenotypic trouble tends to show up in very specific cell types and lineages for each disease (even though these are somatic mutations), for reasons that are not well understood. Many of the trinucleotide repeat diseases have been documented as getting slightly worse in each generation as well (“anticipation”) as the repeats grow larger.

A lot of the work in this field has focused on the proteins and their polyglutamine residues, which is natural enough – that’s generally the “business end” of a lot of genetic diseases, of course (dysfunctional proteins). But there have been clues over the years that at least some of the trouble starts back at the properties of the DNA. That 35-repeat threshold, for example, could be argued either way, but it’s for sure that these repeats can lead to DNA hairpins, triple-helix snarls, unwound regions (sometimes with RNA joining in on one strand, a so-called “R loop”, and more. Now this new paper puts all the evidence together in one place that it’s the CAG problem and not so much the glutamine problem.

They find that the onset of disease for a specific repeat length turns out to be correlated with somatic variations in a number of DNA-repair enzymes, for one thing. And there’s the recent discovery of the details of a spinocerebellar ataxia disease that has CAG repeats but whose protein product doesn’t express the glutamines at all. The etiology is still quite messy, but it’s mostly back at the DNA level:

Ultimately, the disease presentation in any of the trinucleotide repeat disorders may depend on a combination of (1) the rate at which CAG repeats expand in the critical target cell type(s), (2) the degree to which modifiers act to influence expansion rate, (3) the threshold somatic expansion size for cellular damage to occur, (4) the mechanism, polyglutamine toxicity or other, by which that somatically expanded repeat causes the cellular damage, and (5) the degree to which the damage mechanism is influenced by modifiers.

That leaves a place for polyglutamine to cause trouble, but its place as the primary driver of these diseases apparently needs to be given up. Splicing, translation, mRNA effects – there are plenty of places for the wheels to come off back before you make the aberrant protein. People have mostly studied DNA repair and maintenance enzyme systems in the context of oncology, but this paper argues that they should be targets for the trinucleotide repeat diseases as well. But you’d want to start early – it’s already known that the duration of the overt-disease phase seems to be independent of the CAG repeat length in general, which suggests that the mechanisms for disease onset are different from the ones that are triggered once it’s underway. But a new approach to therapy for these conditions is definitely worth paying attention to. As it is, almost all of them have no treatments available at all, so if there’s progress to be made by building on the work done in oncology, then so much the better.

16 comments on “Huntington’s and Other Repeat Disorders: DNA, Not Protein?”

  1. loupgarous says:

    “Spicing, translation, mRNA effects…”

    You meant “splicing”, right, not “spicing”, Derek?

    1. Benjamin says:

      You need to get those mutations somehow. Why not with spice? After all, it worked so well in the Dune universe… 🙂

    2. Hap says:

      It’s a new flavor of Tabasco sauce. “Chipotle Tabasco, now with added spicy DNA, for that extra kick.”

    3. Derek Lowe says:

      Well, yeah, I guess I do, but I’m almost reluctant to fix it. . .

      1. loupgarous says:

        You have a point. Having had “authentic</i<" Jamaican ginger beer once in London, I'm not sure the DNA in the lining of my mouth survived unaltered.

  2. Stephen says:

    Out of my area, but is there a possibility for say CRISPR or RISC to look for these repeat units and eliminate or block them?

    1. Fuhdge says:

      Mostly out of my area too, but from my limited understanding: both the (a) guide RNA that a Cas would use in CRISPR and (b) an siRNA that the RISC would use in RNAi only match ~20 nucleotides and ~22 nucleotides respectively. Therefore, they’re too small to uniquely recognize the large repeats. Moreover, in CRISPR, the Cas can only recognize a sequence next to a protospacer adjacent motif (PAM) so you’d need a proper Cas to recognize the repeat sequence (e.g. for S. pyrogens Cas9, the most popular one in basic research, needs an NGG motif, which means it couldn’t just recognize the repeats alone).

      Also, I know there are big chunks of our genome that are repeat sequences. I’m not sure if they’re the same as the disease-associated repeats we’re talking about here, but it might not be the best idea to go around cutting those sequences up in the CRISPR case.

      Regardless, there are ASOs in the clinic already targeting Huntington at the mRNA level (see Ionis and Roche’s RG6042 aka Ionis HTT-Rx). Phase 1/2 trial with the drug lowered Huntington in the CSF (NCT02519036). Phase III trial is recruiting. There are other plays out there as well. We’ll see how it goes.

  3. Brandon Berg says:

    In addition to trinucleotide repeats, there are also hexanucleotide repeats. Notably a GGGGCC repeat in C9ORF72 is the most common identified cause of familial ALS.

  4. sgcox says:

    It may still be RNA, not DNA or protein – as far as understand these 3(6) repeats are transcribed.

    1. Charles U. Farley says:

      Nope – some disease causing repeats are intronic, some are in promoters! Fascinating stuff.

      1. MD/PHD says:

        Introns are transcribed. Also promoter mutations could obviously be impacting the amount of RNA generated. Important to keep in mind other ideas but it looks like there are already signals of HD-disease modification with the Roche/Ionis ASO.

  5. Mol biologist says:

    The number of repeat *at some range” is not such critical compared to genomics background which can eliminate toxic effect of repeats. It calls the ‘gray area’ of genetics and I will call it “spice”.
    The clinical meaning when the HD gene has a repeat length between 27 and 39 CAGs – often described as the ‘gray area’. People with an HD gene containing between 36 and 39 repeats are in the ‘reduced penetrance’ range. Some people in this range will develop symptoms of the disease, while others won’t.
    Unfortunately, currently, it’s impossible to predict who isn’t. It is even more “spicy” because in some dominant form of cardiomyopathy the presence of the mutation isn’t always a factor which can lead to disease development. BRAC1/2 mutation carriers have only 50% or less risk to develop some forms of cancer and this is still “grey area” too. IMO what is really “spicy” is Derek’s persistence in the area of neurodegenerative diseases, isn’t it?

    1. CO says:

      I would say anyone with gray hair has a substantial personal stake in the progress of neurodegenerative diseases.

  6. hn says:

    I went through the literature 20 years ago when I was a graduate student looking for a research problem. After all this time, I am disappointed that researchers still haven’t resolved whether the disease is due to problems with DNA, RNA, or protein.

    1. Mol biologist says:

      May be you need a little more time? 10 or 20 more years?

  7. feather says:

    So, is the HTTrx to target CAG repeat of the mRNA of the huntingtin gene?

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