A recent study on Spinocerebellar Ataxia type 12 or SCA12 has provided key insights into how genetic changes affect brain function and contribute to neurodegeneration. SCA12 is a debilitating neurological disorder that leads to tremors, walking difficulties, and problems with coordination and balance.
More prevalent in certain communities in North India, it typically manifests later in life and primarily affects the cerebellum, which controls motor functions and also impacts mental health, suggesting that multiple brain regions are involved in both neurological and psychiatric symptoms.
The March 2025 study titled 'CAG Repeat Instability and Region-Specific Gene Expression Change in the SCA12 Brain' published in Springer Nature delves into the instability of the CAG repeat sequence and its varying effects in different brain regions. CAG repeats occur in many genes and are a genetic sequence of three DNA building blocks—Cytosine, Adenine, and Guanine—that repeat many times. When this repeating sequence gets too long, it can lead to neurodegenerative diseases, like Huntington's disease and SCA.
The study findings suggest that protecting DNA from mutations in brain cells could offer a viable treatment strategy for SCA12. It is the first published work in the world to demonstrate somatic mosaicism in the SCA12 brain. When multiple genetically distinct populations of cells occur within an individual due to a mutation after fertilization, it is referred to as somatic mosaicism.
What causes SCA12?
SCA12 is caused by a mutation in the PPP2R2B gene located on chromosome 5. The PPP2R2B gene is a blueprint within a person's body that helps control a special enzyme called protein phosphatase 2A (PP2A), which helps control many important functions in cells, including those in the brain.
SCA12 is the second most common type of Spinocerebellar Ataxia in India, with studies indicating a prevalence rate of 25% among SCA cases. A large portion of SCA12 cases in India occurs within one community, an ethnic group from northern India that practices endogamy. In this community, SCA12 accounts for 56% of all SCA cases. While approximately 25% of SCA12 cases are reported from North India, the condition has also been found in South and West India.
What does the new research say?
Conducted over 1-2 years using a brain donated by the family of a deceased individual with SCA12, the study required a multidisciplinary approach, with researchers examining gene repeats in the PPP2R2B gene and DNA methylation (a chemical modification) patterns across various brain regions.
Speaking to ETV Bharat, Professor Emeritus Sanjeev Jain from the Psychiatry Department at NIMHANS who is one of the authors of the study, said their research findings suggest a potential treatment strategy focused on stabilizing DNA repeats as a promising approach for managing SCA12.
"Using advanced sequencing technologies, we explored how genetic changes affect brain function and contribute to neurodegeneration. Unlike mutations that cause cancer, the mutation in SCA12 leads to neurodegeneration," he explained.
"We utilized high-end sequencing technology to study how genetic changes in the brain lead to neurodegeneration, offering insights into potential treatment strategies that could prevent mutation and repair damaged brain cells," Jain said, adding that the research paves the way for both clinical treatment and advanced genetic studies.
CAG repeat size varied across multiple brain areas
The researchers observed that the cerebellum, which is the primary target in SCA12, exhibited the least repeat instability, which was correlated with more methylation and reduced gene activity. Notably, genes responsible for DNA repair were more active in these areas, potentially helping to mitigate DNA instability.
However, genes regulating the cell cycle showed reduced activity, which could contribute to cell death and the brain damage seen in SCA12. This defence mechanism against instability might come at the cost of increased neuronal cell death, leading to degeneration over time. Specifically, Purkinje neurons, which are essential for movement coordination, were found to be fewer in the cerebellum of the SCA12-affected brain.
Earlier studies highlighted the cerebellum's vulnerability in SCA12, showing significant nerve cell loss and shrinkage, which resembles neurodegeneration observed in Huntington's disease (HD). In both conditions, the size of the gene repeat, which correlates with the severity of symptoms, is also seen to vary across different brain regions.
Researchers observed higher repeats in different brain regions
In the study, it was found that the brain of the SCA12 patient exhibited sequence reads with 60 CAG repeats and more, far higher than the 55 repeats that had been reported at the time of genetic testing of his blood.
The researchers observed higher repeats in different brain regions, highlighting a phenomenon called repeat instability leading to somatic mosaicism, where the CAG repeat length varied in different areas of the brain. If the CAG repeat exceeds a certain threshold, the brain is unable to cope, leading to rapid neuronal death.
Dr Meera Purushottam, Senior Consultant at the Molecular Genetics Lab in the Department of Psychiatry at NIMHANS, in an exclusive conversation with ETV Bharat, explained SCA12 and how it was caused by mutations in a specific gene.
“SCA12 is caused by mutations in the PPP2R2B gene. It is a type of Trinucleotide repeat expansion disorder, which refers to genetic conditions caused by the abnormal expansion of three-nucleotide DNA sequences. This leads to a range of neurological, developmental, and neuromuscular issues, with expanded CAG repeats in particular genes being more common. In SCA12, expanded CAG repeats in the PPP2R2B gene might lead to abnormal protein production, which disrupts the normal function of nerve cells in the spinal cord and cerebellum, eventually causing their degeneration,” Dr Purushottam stated.
She explained that while everyone has a certain number of CAG repeats in their DNA, when these repeats become excessive, they become disease-causing.
Root cause of CAG repeat expansion
Dr Meera further explained the root cause of the CAG repeat expansion, noting that the defect in DNA is linked to its inherent nature, and during replication, the molecules tend to form abnormal structures that cause slippage.
"It’s a basic concept that all cells have the same DNA, but gene expression can vary depending on the cell’s function. For example, neurons and skin cells express genes differently. Somatic mosaicism occurs when there is variation in the DNA sequence of cells. Sequencing revealed that in the cerebellum, there was less gene expression, DNA modification, and overexpression of certain genes, with some cells showing no expression at all," she added.
Meera emphasized that understanding these regional differences in gene expression could lead to more precise treatments, such as drugs that can repair DNA and slow the rate of CAG repeat expansion. Instead of pursuing complicated options like gene therapy and clinical trials, she suggested that repurposing drug molecules could be a more viable pathway to address the issue.
She concluded by emphasizing the importance of organ donations, particularly brain donations. "People are often reluctant to donate organs after the death of a loved one, but such donations are invaluable for scientific progress. Encouraging brain donations is crucial, as they help us better understand the disease and develop remedies. With advancements in technology and access to resources, much can be achieved in our country."
This research marks a significant step forward in understanding SCA12 and offers hope for future treatment strategies that could alleviate symptoms or even prevent the disease manifestation.
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