Written by Dr. Sriram Jayabal Edited by Dr. Ray Truant

A potential new pathway for SCA17: gene therapy that in mice restores a critical protein deficit protects brain cells from death in SCA17.

Neurodegenerative ataxias are a group of brain disorders that progressively affect one’s ability to make fine coordinated muscular movements. This makes is difficulty for people with ataxia to walk. Spinocerebellar ataxia type 17 (SCA17) is one such late-onset neurological disease which typically manifests at mid-life. The life expectancy after symptoms first appear is approximately 18-20 years. Besides ataxia, SCA17 can cause a number of other symptoms ranging from dementia (loss of memory), psychiatric disorders, dystonia (uncontrollable contraction of muscles), chorea (unpredictable muscle movements), spasticity (tightened muscles), and epilepsy.

Brain imaging and post-mortem studies have identified that the cerebellum (often referred to as the little brain) is one of the primary brain regions that is affected. That being said, other brain regions such as the cerebrum (cortex or the big brain) and brainstem (distal part of the brain found after the cerebellum) could undergo degeneration. Further, the genetic mutation that leads to SCA17, is a CAG-repeat expansion mutation, similar to several other forms of ataxias. In most other ataxias, where the function of the mutated protein is unknown. However in SCA17, the function of the mutated protein, TATA-box binding protein, is very well understood. Despite this unique advantage, we are yet to completely understand how the mutant gene leads to SCA17. This is why current treatment strategies often focus on treating the symptoms, but not the underlying cause.

SCA17 mutation leads to Purkinje cell death

Researchers from China have shed more light on how the mutant gene causes SCA17. TATA-box binding protein is a transcription initiation factor is a protein that turns on the production of RNA from genes. It is widely found across the brain including the cerebellum. TATA-box binding protein controls the amount of protein manufactured from several genes. This raised a very important question: pertinent not only to SCA17 but also more generally to several SCAs – why is that the cerebellar neurons, especially the most sensitive neuron, the Purkinje cells die?

To understand this, the researchers used state-of-the-art genetic engineering viral technology to artificially introduce mutant-TATA-box binding protein in different brain regions of healthy mice including the cerebellum. The researchers found that cerebellar neurons exhibited a lot of cell death compared to neurons in other tested brain regions. Neurons in other brain regions had little to no cell death. This is exciting as it suggests that perhaps there is something unique about the cerebellar Purkinje neurons which makes them more susceptible to mutant-TATA-box binding protein than other neurons in the brain.

Since this mutation is artificially introduced in healthy mice, researchers next set out to confirm these results in a mouse model of SCA17. In these mouse models, the mutant-TATA-box binding protein is inherited from their parents. This is similar to how the disease is acquired in humans. They found that in SCA17 mice mutant-TATA-box binding protein led to the death of mostly the cerebellar Purkinje neurons. Taken together, these results strongly suggest that the mutant protein is responsible for the cell death seen in SCA17. 

Why do Purkinje cells mostly die?

The researchers wanted to identify the unique molecules that make Purkinje cells very sensitive to mutant-TATA-box binding protein. To do this, they performed a transcriptome analysis where you examined all gene readouts produced in a cell. They used this to compare SCA17 and healthy cerebellum, as well as other brain regions to screen for potential differences. By conducting such a thorough screening, they found that the disease-cerebellum which harbored mutant-TATA-box binding protein exhibited abnormal levels of many proteins compared to a healthy-cerebellum. To further narrow down, they focused on proteins that are uniquely found in the cerebellum compared to other brain regions. They found that a protein called Inositol Polyphosphate-5-Phosphatase (Inpp5a) was decreased specifically in the cerebellum. Low levels of Inpp5a in mice has been shown to lead to ataxia in previous studies.  

Next, the researchers wanted to directly test if Inpp5a can lead to predominant Purkinje cell death. To do this, they used another gene-editing tool to very precisely reduce the level of Inpp5a protein in healthy mice. This led to the predominant loss of Purkinje cells, thus confirming that the mutant-TATA-box binding protein dependent reduction in the Inpp5a protein levels makes the Purkinje cells more susceptible to cell death.

Inpp5a: A potential new pathway in SCA17

If the reduction in Inpp5a renders Purkinje cells more susceptible, then restoring normal levels of Inpp5a protein in SCA17 mice might protect the Purkinje cells from cell death. To test this, researchers used gene therapy to increase the levels of Inpp5a protein in SCA17 mice, which prevented the Purkinje cells from dying. Over the past few years, using gene therapy to manipulate the levels of proteins that are mutated in SCAs directly has garnered increasing attention, and such therapies have been tested for several SCAs including SCA1, 2, 3, and 6.

Here, the researchers rather than taking an approach to inhibit expression of the mutated protein directly, they instead opted to test the impact of increasing Inpp5a protein. This strategy protected the Purkinje neurons. These results show that there are other genes that can be important for this disease other than the mutated TATA-box binding protein gene in SCA17, which means a new approach for therapies.

What’s in store next? 

This study answered some questions and raised many other important questions. A new role was identified for a cerebellum-enriched protein, Inpp5a in SCA17. Normal levels of this protein are needed for the survival of cerebellar Purkinje neurons – reduced levels of Inpp5a leads to the death of Purkinje cells in SCA17. Further, increasing the levels of Inpp5a prevents Purkinje neuron degeneration. Future experiments are needed to reveal the exact reasons why increasing Inpp5a was beneficial.

Despite gaps in knowledge, which the future research will address, this study is critical as it has identified a new pathway that causes cell death in SCA17, which could be targeted to achieve potential therapeutic benefits.

Key Terms

Cerebellum: A primary area of pathology in the spinocerebellar ataxias. This brain region sits toward the back of the skull and, though small in stature, contains the majority of the nerve cells (neurons) in the central nervous system. Contains the circuits that fine-tune our movements, giving us the ability to move with precision. Learn more in our Snapshot on the Cerebellum.

Purkinje Neurons: A type of neuron in the cerebellum. They are some of the largest cells in the brain. They help regulate fine movement.  Purkinje cell death is a common feature in cerebellar ataxia. Learn more about them in our Snapshot on Purkinje Cells.

Conflict of Interest Statement

The author and editor declare no conflict of interest.

Citation of Article Reviewed

Liu Q, Huang S, Yin P, Yang S, Zhang J, Jing L, Cheng S, Tang B, Li XJ, Pan Y, Li S. Cerebellum-enriched protein INPP5A contributes to selective neuropathology in mouse model of spinocerebellar ataxias type 17. Nature Communications. 2020 Feb 27;11(1):1-3.(https://www.nature.com/articles/s41467-020-14931-8)