Information was consolidated here that used to be elsewhere on this blog, then expanded. This page is highly specific to SCA3, which I have.
In the beginning…
The neurons (brain cells) in the cerebellum initially form at the 6th or 7th week of embryonic development, just before the fetal stage, and with SCA3, they form with the genetic defect present. The brain continues to add neurons throughout the fetal stage, but after birth, brain weight is increased mainly through glial cell division.
Later in life after the cerebellum matures and the defective gene is expressed in it for a few decades, the toxic protein that the defect creates causes the cerebellum to noticeably degenerate (it may also affect cerebellar development). The defective DNA is present in the nucleus of all cells in the brain and body but causes a problem mostly in the cerebellum.
If neurons deteriorate, then the hope is that they can be recovered. If neurons die, then they cannot be recovered; except for a few exceptions, neurons are formed only during embryogenesis and are not replaced later.
I don’t think that the onset of external symptoms tells us when cerebellar degeneration became significant. It could be that the degeneration begins earlier in life and caves in on itself—so to speak—later in life, as the protein is not only toxic but also gums up the works: hampering autophagy—the cell-level cleanup process—which means that as cells die, their residue can cause other cells to die.
There are six SCAs that involve CAG repeats: 1, 2, 3, 6, 7, and 17; they are referred to as the polyglutamine forms of SCA. Why? To begin with, you can look up CAG in the DNA codon table:
Of the 43 possibilities, CAG is the coding for glutamine, which is an amino acid used in protein synthesis. When many glutamine repeats cause a disease, that disease is known as a polyglutamine disease. Glutamine can be abbreviated simply as Q, hence the term polyQ.
Aside: since DNA is translated to RNA and the RNA creates the toxic protein, it’s important to note that the CAG repeat in the DNA does ultimately end up in the RNA:
C-G-A-T are known as DNA nucleotides. Polyglutamine diseases can also be known as trinucleotide repeat [expansion] diseases and triplet repeat [expansion] diseases. Since a repetitive tract of DNA can generally be called a microsatellite, the term microsatellite repeat expansion (MRE) might be used. In other words, the polyQ SCAs are also known as MRE diseases.
The Times They Are a-Changin’
Even with a specific diagnosis of SCA3, which I have, different people can have vastly differing experiences based on (among other things) their specific number of CAG repeats.
The rule here is: a longer CAG repeat length means an earlier age of onset. For about 25 years, I was “taught” that an earlier age of onset meant faster cerebellar degeneration. However, now it seems only the first part of that is true (for SCA3):
It’s also interesting to note that SCA3 has been clinically divided into five sub-types. In short, a high CAG repeat count does mean an earlier age of onset, but rather than the same list of symptoms coming on faster or slower, it’s a differing list of symptoms, and there still might be bit of stronger or weaker overall severity.
Fitting into these genes
If you take a step back, the gene containing the CAG repeat (in the case of SCA3) is called ATXN3, and the protein (an enzyme) that the gene is responsible for constructing is called ataxin 3. Ataxin 3 is expressed throughout the body and brain. When the gene has aberrant CAG repeats, the protein becomes toxic mainly to the cerebellum. The toxicity of the protein comes from misfolding and aggregation.
Ataxin 3 is expressed ubiquitously, which means—in the brain—it’s found in both neuronal and non-neuronal cells (i.e., glial cells). Furthermore, mutant ataxin 3 is toxic (i.e., causing dysfunction) in both places. While the actual result of toxicity is different in both cases, they both contribute to the problem.
Ataxin 3 is known as a deubiquitinating enzyme, or DUB [see also]. It is involved in the ubiquitin-proteasome system that destroys and gets rid of excess or damaged proteins. The molecule ubiquitin binds to unneeded proteins and tags them to be degraded (broken down) within cells. Ataxin 3 cleaves (removes) the ubiquitin from these unwanted proteins just before they are degraded so that the ubiquitin can be used again.
Because ataxin 3 is used throughout the body, I assume that if its presence were missing, the body would malfunction.
Sanity check: cells are molecularly huge! The human genome encodes about 20,000 different proteins, and the average cell contains about 10,000 proteins (some the same type, some different). The point is that for a ubiquitously expressed protein, it’s unlikely that you won’t find it expressed, even among thousands of other proteins.
For more information about normal vs. abnormal protein function, see here.
How old is the toxic protein? While your neurons are slightly older than you consider yourself to be, most proteins contained in the neurons range from hours to days old. Since SCA3 has an adult age of onset, I’m guessing this means it takes a few decades for the dynamic toxic protein churn to begin really gumming up the works, and then a few more decades to cause major damage.
Location, location, location
The precise gene location of the SCA3 defect is not important to know. The only reason I’m mentioning it is that it brings up a terminology issue that’s mildly interesting. The cytogenetic location—AKA locus—of the ATXN3 gene is 14q32.12, and here’s how to read it:
- The chromosome is 14 (of 22); the sex chromosome (#23, if you will, which is either XX or XY) is not numbered with the rest.
- The arm is one of two letters: p (short) or q (long). It’s the “q arm” in this case.
- The region is 3, and the band is 2—not “thirty-two” but “three-two.”
- The sub-band is 1, and the sub-sub-band is 2—not “twelve” but “one-two.”
Thus, the whole thing reads as “fourteen q three-two point one-two.”
Coming to terms
Some useful terms to be aware of:
- Stress granule: dense protein aggregation.
- Cytosol: the liquid inside cells, where stress granules occur.
- RNA foci: this seems to be a reference to where in the RNA the focus of trouble begins, due to the polyQ expansion.
- Purkinje cells: neurons in the cerebellum.
- Anticipation: a common phenomenon whereby as (e.g.) a trinucleotide repeat disorder is passed on to the next generation, the number of repeats increases.
- Allele: human cells are diploid, meaning they have two sets of (23) chromosomes, one set from each parent. At some gene locations, the chromosomes are the same (homozygous). At other locations, the chromosomes are different (heterozygous). Those gene locations are known as alleles.
- Protein folding: the physical process by which a protein chain acquires its native three-dimensional structure.
- Proteopathy: a class of diseases (including SCA3) caused by protein misfolding.
- Gene is to genome as exon is to exome. Genes consist of exons and introns. Exons (about 1.5% of the genome) code for proteins, whereas introns do not. Introns are ultimately excluded from the RNA translation process.
- This can come up in the area of gene sequencing. It can be cheaper to get a smaller whole exome sequence (WES) rather than a larger whole genome sequence (WGS).
- But… Friedreich’s ataxia (FA) is the result of an intron defect. FA is also a triplet repeat disease, but rather than resulting in a toxic protein like with SCA3, FA causes DNA-to-RNA transcription failure, and ultimately abnormal gene silencing—i.e., a protein that should be created is not.