SCA3 is one of the “polyglutamine diseases” (PolyQ disorders)

SCA3 occurs when the allele (copy) of the ATXN3 gene inherited from one of the parents contains a mutation with an abnormally high number of CAG trinucleotide repeats (cytosine, adenine, guanine), which code for the amino acid glutamine (Q) in the protein produced by the gene. This causes the mutant protein to have an abnormal conformation, with an excessive polyglutamine (PolyQ) expansion. This malformed protein tends to accumulate and form aggregates, especially within the nuclei of nerve cells (neurons).

​

Nature has protective mechanisms to “clean up” cells by breaking down problematic or unnecessary proteins. However, for some reason, these mechanisms fail to properly degrade polyglutamine aggregates, which are insoluble by natural cellular methods. As a result, the defective proteins become toxic, leading to dysfunction in vital cellular processes such as autophagy, DNA transcription, axonal transport, and protein homeostasis, ultimately causing degeneration and death of cerebellar neurons (and other nervous system cells). The symptoms of ataxia result from this neuronal loss.

​

The pathogenesis of SCA3 involves multiple pathological mechanisms:

• Toxic gain of function: The mutant ataxin-3 forms protein aggregates and nuclear inclusions that impair protein homeostasis and contribute to neuronal dysfunction.

• Loss of function: The mutation in ataxin-3 leads to a reduction in its deubiquitinase activity, impairing the cell’s ability to degrade misfolded proteins and potentially exacerbating the accumulation of toxic aggregates. In short, deubiquitinase activity refers to the protein’s ability to remove ubiquitin molecules from other proteins, which protects them from degradation via natural pathways.

 

Note: In addition to the protein-related effects described above, there is also the possibility that RNA transcribed from the ATXN3 gene with expanded CAG repeats may have toxic effects. These expanded CAG repeats can lead to the formation of abnormal secondary RNA structures, which may impair RNA splicing regulation (*) and, as a result, interfere with gene expression, contributing to neuronal degeneration. In SCA3, however, the experimental evidence for RNA-mediated toxicity is still considered emerging, and further studies are needed to determine the extent of its role in disease pathogenesis.

​

(*) Splicing is the process by which the newly transcribed messenger RNA (mRNA) undergoes removal of introns (non-coding regions) and joining of exons (coding segments), forming the mature mRNA that will be translated into protein.

​

Additional Notes on PolyQ Disorders

(Adapted from “Pathogenesis of SCA3 and implications for other polyglutamine diseases”, Hayley S. McLoughlin et al., 2020) [8]:

 

1. Currently, nine PolyQ diseases have been identified, including Huntington’s disease (HD), Dentatorubral-pallidoluysian atrophy (DRPLA), Spinal and Bulbar Muscular Atrophy (SBMA), and six types of spinocerebellar ataxias (SCAs)—specifically SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17. All of these disorders are caused by expanded CAG repeats within coding regions of their respective genes and share several common features: 

• All PolyQ diseases (except for SBMA, which is X-linked) have autosomal dominant inheritance.

• They primarily affect the central nervous system (CNS), although peripheral nerves and muscles may also be involved.

• They are progressive and evolve over several years.

• All PolyQ disorders show an inverse correlation between the length of the CAG expansion and the age of onset and severity of symptoms, and may exhibit the phenomenon of anticipation as previously discussed.

 

2. In PolyQ diseases, the malformed proteins with excessive glutamine (CAG repeats) tend to aggregate, mainly within the nuclei of neurons, although cytoplasmic and even axonal aggregates may also occur. The exact significance of these nuclear protein aggregates remains unclear. One hypothesis suggests that aggregation may initially be neuroprotective, but over time becomes toxic (pathogenic), as it leads to the sequestration of essential proteins, including transcription factors. Aggregates also damage mitochondria, the chaperone system (a group of proteins that assist in the correct folding of other proteins), and the UPS (ubiquitin-proteasome system), which regulates the degradation of unwanted or damaged proteins. Autophagy, a cellular protein quality control mechanism, is also impaired. In addition, DNA repair processes in the cell nucleus may be affected. All these disruptions compromise neuronal function and may ultimately lead to neuronal death.

​

3. In addition to neurons, other cell types such as glial cells—including astrocytes, microglia, and oligodendrocytes—may also play an important role in the pathogenesis of spinocerebellar ataxias and other PolyQ diseases. For example, glial cells (e.g., Bergmann glia) have been shown to play a significant role in the degenerative process in SCA7. Observed changes in glial cells in animal models of SCA1 and Huntington’s disease may reflect a common feature of other PolyQ disorders as well.

 

Diagnosis - The diagnosis of SCA3 can be confirmed through molecular genetic testing (DNA analysis) to detect abnormal CAG expansions in the ATXN3 gene. This is especially recommended when there is a positive family history of SCA3 (i.e., a relative with a confirmed diagnosis). Before ordering genetic tests, neurologists typically perform clinical neurological examinations to assess symptoms, reflexes, eye movement abnormalities, family history, etc. It is also common to request neuroimaging (e.g., MRI) to check for signs of cerebellar and pontine atrophy.

​

Note: Although obtaining a genetic diagnosis can be challenging, it is important because it enables better genetic counseling for family members (regarding the risk of passing the mutation to future generations), supports more accurate disease management, and may allow the patient to participate in clinical trials for emerging treatments targeting specific types of ataxia.