SCA2 is one of the Polyglutamine (PolyQ) Diseases. SCA2 occurs when the allele (copy) of the ATXN2 gene, inherited from one of the parents, contains a mutation with an abnormal number of CAG trinucleotide repeats (cytosine, adenine, guanine), which encode the amino acid glutamine (Q) in the resulting protein. This leads to the production of a misfolded protein with an excessive polyglutamine expansion. This abnormal 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 unknown reasons, these mechanisms do not function properly with polyglutamine aggregates, which are insoluble through natural processes. As a result, these defective proteins become toxic, potentially disrupting vital cellular processes such as autophagy, DNA transcription, axonal transport, and protein homeostasis, ultimately leading to the degeneration and death of cerebellar neurons (and other nervous system cells). The resulting neuronal loss gives rise to the symptoms of ataxia.

​

Additional Notes on PolyQ Disorders

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

 

1. Currently, nine PolyQ disorders 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): SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17. All of these conditions are caused by expanded CAG repeats in coding regions of their respective genes and share common features. For example:

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

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

• They are progressive over the course of several years.

• In all PolyQ disorders, there is an inverse correlation between the size of the CAG expansion and the age of symptom onset and severity, with the possibility of anticipation (earlier and more severe symptoms in successive generations).

 

2. In PolyQ diseases, misfolded proteins with excess glutamine repeats tend to aggregate mainly within the nuclei of neurons, although cytoplasmic and even axonal aggregates may also occur. The exact role of these nuclear aggregates is still unclear, but one hypothesis suggests that while initially neuroprotective, they eventually become toxic (pathogenic), sequestering essential proteins such as transcription factors and damaging key systems, including:

These combined issues impair normal neuronal function and may lead to neuronal death.

• Mitochondria

• The chaperone system (which assists with protein folding)

• The ubiquitin-proteasome system (UPS) (which degrades unwanted or damaged proteins)

• Autophagy (the cellular “quality control” mechanism)

• DNA repair within the cell nucleus

 

3. In addition to neurons, other cell types such as glial cells (astrocytes, microglia, and oligodendrocytes) may also play important roles in the pathogenesis of spinocerebellar ataxias and other PolyQ diseases. For example, Bergmann glia are known to play a key role in the degenerative process in SCA7, and glial changes observed in animal models of SCA1 and Huntington’s disease may represent a common feature of PolyQ diseases.

​

Diagnosis - The diagnosis of SCA2 can be confirmed through molecular genetic testing (DNA analysis) to detect abnormal CAG expansions and CAA interruptions in the ATXN2 gene. Testing is especially recommended when there is a positive family history of SCA2 (i.e., a relative with a confirmed diagnosis). Before ordering genetic testing, the neurologist typically conducts clinical neurological examinations to assess symptoms, reflexes, eye movement abnormalities, and family history, and may also request neuroimaging to check for signs of cerebellar atrophy, for example.

 

​Note: Although genetic diagnosis may be challenging, time-consuming, and expensive, it is important because it enables:

• Better genetic counseling for family members (regarding the risk of mutation transmission to future generations);

• More accurate disease management, since the condition will be well-defined;

• Eligibility for participation in clinical trials for specific ataxia treatments.