A Cerebellar Paradox Offers Clues in SCA12 Research

Genetic stutters echo through the brain, but their impact is far from uniform. A surprising resilience in the cerebellum is rewriting our understanding of SCA12's complex pathology.

(L-R) Dr Meera Purushottam, Senior Consultant & Shreevidya Parthaje, PhD Scholar, Molecular Genetics Lab, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru (NIMHANS)

A recent study published in The Cerebellum by Dr Meera Purushottam’s team at the Molecular Genetics Laboratory, NIMHANS, Bengaluru has unveiled significant regional variations in the molecular pathology of Spinocerebellar ataxia type 12 (SCA12), a debilitating neurological disorder, caused by an expansion of repetitive CAG sequences in the PPP2R2B gene.

Imagine DNA as a long, intricate sentence. In SCA12, a particular word – CAG – is repeated far more often than it should. This "stutter," or expansion, is associated with the disease. But is the length of this stutter consistent throughout the brain? Researchers used DNA obtained from the  post-mortem brain donation of a patient diagnosed with SCA12. The study examined CAG repeat length, gene expression, and DNA methylation patterns across multiple brain regions. What they discovered was a dramatic difference in the stability of these CAG repeats. Some brain cells have longer CAG repeats than others. Surprisingly, the DNA from cerebellum (the brain region primarily responsible for coordination and balance), showed the least degree of CAG expansion and somatic instability.

Is this tissue extra resilient? Researchers found that the cerebellum seemed to be employing a sort of molecular defence. They observed decreased PPP2R2B gene expression and increased DNA methylation within this region. Interestingly, the cerebellum also exhibited high expression of genes involved in DNA maintenance and repair pathways. This implies enhanced mechanisms within the cerebellum, to perhaps prevent slippage and restrict CAG expansion errors. The study also examined the expression of genes involved in cell cycle regulation and found altered expression patterns. These disruptions may contribute to the hallmark neuronal loss and cell death seen in neurodegenerative diseases. 

This study highlights a complex interplay between CAG repeat instability, gene expression and cellular processes in SCA12, indicating the importance of studying regional differences in molecular pathology. Future research can focus on drugs that enhance DNA repair or promote repeat stability. While SCA12 remains a challenging condition, these findings offer new hope and a deeper understanding of the brain's hidden battle against this devastating disorder.

Access the full publication here: CAG Repeat Instability and Region-Specific Gene Expression Changes in the SCA12 Brain