What role do brain alterations play in the onset and progression of spinocerebellar ataxia type 6 (SCA6)? While previous studies highlighted cerebellar changes in individuals with SCA6, the underlying mechanisms and their connection to when symptoms manifested and how the disease advanced were unclear—until now. 

As reported by McGill University, a team of the University’s researchers sought out to find answers. The research team began by performing RNA sequencing on cerebellar vermis tissue in mice models of spinocerebellar ataxia type 6. Through this, the research team identified gene dysregulation within the models’ endo-lysosomal systems. These alterations contributed to:

• Enlarged early endosomes and smaller late endosome compartments 
• Impaired trafficking of cargo (proteins) to the lysosomes 
• An accumulation of brain-derived neurotrophic factor and tropomyosin kinase B in early endosomes 

These findings were compelling as they had never been observed before. But researchers believed that endosomal dysfunction played a role in SCA6 pathology. 

In research published in eLife, the researchers explain that, following these findings, they treated the mice models with a tropomyosin kinase B agonist called 7,8-dihydroxyflavone. The treatment showed significant promise in the mice models. 7,8-dihydroxyflavone moved proteins to where they should be located, reducing trafficking impairments and allowing for increased signaling. 

This study is considered pre-clinical. While identifying the endosomal dysfunction in SCA6 is incredibly important, and researchers could use this to develop targeted treatment, more research is needed to better understand these mechanisms and potential disease interventions.

Understanding Spinocerebellar Ataxia type 6 (SCA6)

There are multiple types of spinocerebellar ataxia, a group of hereditary conditions characterized by nervous system damage. This damage, which occurs in the portion of the brain that controls movement, causes progressive movement issues. 

CACNA1A gene mutations cause spinocerebellar ataxia type 6. According to the National Ataxia Foundation, the age of onset differs significantly, from 19 to 72 years old. The most common age of onset is between 43-52 years old. Symptoms and severity vary but may include: 

• An unsteady gait
• Problems with balance and coordination
• Nystagmus (involuntary eye movements)
• Speech difficulties such as slurred speech
• Tremor
• Double vision 
• Loss of coordination in the limbs
• Uncontrolled muscle tensing 
• Difficulty swallowing (in later stages) 

If you have SCA6, you are not alone. Consider joining the SCA-6 Ataxia Support Group on Facebook.