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Clearing aggregated ataxin-2 protein as a therapeutic avenue for SCA2

Written by Dr. Vitaliy Bondar Edited by Dr. Hayley McLoughlin

New research suggests that mutant ataxin-2 protein overwhelms cells in SCA2, leading to decreased autophagy and clearance of damaged proteins.

Many comparisons can be made between cells and human beings. Just like humans, cells can accumulate junk and waste at certain times and this clutter overtime becomes problematic and even toxic. This is precisely what Jonathan Henry Wardman and colleagues from the University of Copenhagen decided to investigate on a cellular level. They asked whether the lack of appropriate clearance of faulty disease proteins effect cellular survival and wellbeing.

The researchers chose to study cells derived from a patient that has Spinocerebellar ataxia type 2 (SCA2). The cause of SCA2 is CAG repeat expansion in the ATAXIN-2 gene, which encodes polyglutamine amino acid chain in an RNA-binding protein, ataxin-2. The faulty polyQ expanded ATXN2 protein is found to aggregate inside the cell and overtime can affect its survival. Accumulation of aggregated protein products derived from mutated genes is a hallmark of many types of spinocerebellar ataxias as well as other forms of neurodegenerative disorders such as Parkinson’s disease.

It is unclear how protein aggregation impacts cellular survival. However, multiple cellular defects have been correlated with ataxin-2 aggregation. For instance, mitochondria which generates energy for a cell, has been reported to abnormally function in SCA2 cellular models. Additionally, a cellular clearance mechanism, called autophagy, which is responsible for clearing faulty cellular compartments and certain broken proteins is shown to be less effective in various SCA2 models. These mechanisms the authors decided to investigate in their recently published research article.

New research using SCA2 cells sheds light on what causes disease symptoms to occur. Photo by Chokniti Khongchum on

The scientists first identified evidence of SCA2 cellular dysfunction through detection of significant elevation of caspase-9 and caspase-8 levels. These are protein which indicate cellular stress and death. The authors hypothesized that such cellular dysfunction may arise from accumulation of faulty ataxin-2. In order to test this hypothesis, they decided to systematically block two cellular pathways that process defective proteins: proteostasis and autophagy.

While inhibiting proteostatic pathway did not correct caspase-8 levels, blocking autophagy made caspase-8 levels go back to normal. Interestingly, inhibition of autophagy, but not proteostasis increased ATXN2 levels. This showed that the autophagy pathway controls ATXN2 turnover. These results suggest two potential outcomes: polyQ expanded ataxin-2 may aggregates due to dysfunction in autophagy pathway or accumulation of aggregated ataxin-2 overwhelms autophagy.

 In order to rule out the first possibility, the authors assessed autophagy pathway in SCA2 cells. They found normal levels of autophagy markers in SCA2 cells. This excluded the first hypothesis, that that faulted ataxin-2 aggregates due to disfunction in autophagy.

Next, the authors tested if activation of autophagy would fix the cellular stress in death seen in SCA2. If autophagy was acting to slowly and being overwhelmed by ataxin-2 protein, then increasing autophagy my fix it. To do this, healthy and SCA2 cells were treated with trehalose, a sugar molecule known to activate autophagy. Just like they had predicted, patient derived SCA2 cells treated with trehalose demonstrated reduced caspase-9 and caspase-8 levels back down. These results suggest that autophagy is the core pathway in regulation of ataxin-2 levels and SCA2 cellular toxicity.

Up to this point, the authors and other researchers studying SCA2 cells had observed three things: (1) disease causing ataxin-2 protein forms aggregates in cells, (2) SCA2 cells have increased signed of cellular stress and death, and (3) autophagy in SCA2 cells doesn’t work like it does in healthy cells. The authors wanted to see if there was a connection between these three observations.

To do this, they treated SCA2 derived patient cells with Congo red. Congo red is a compound previously that helps dissolve aggregated proteins in other neurodegenerative diseases. They found that Congo red significantly reduced cellular stress and death effects seen in SCA2 cells. In SCA2 cells, there are usually increase levels of total ataxin-2 protein. However, in Congo red treated SCA2 cells total ataxin-2 levels were brought back to the levels seen in healthy cells. They didn’t see any changes in autophagy between Congo red treated cells and untreated in both unaffected and SCA2 derived cells.

These results suggest that aggregation of polyQ expanded ataxin-2 is the primary cause of activation of cellular stress and death pathways. Autophagy plays an important role in clearing ataxin-2 aggregation, and based on this study, unlikely to play a primary driving force in SCA2. It is likely that autophagy is impaired due to aggregation of ataxin-2, which overtime gives rise to additional cellular defects we see such as deficiency in clearance of other damaged proteins and cellular compartments.

Moving forward it will be important to study the molecular mechanism for how ataxin-2 impedes normal cellular function to eventually cause its demise. Likewise it will be important to understand how we may use cellular clearance pathways such as autophagy to increase removal of polyQ expanded ataxin-2. Further, the findings in this study may be relevant to other types of spinocerebellar ataxia and neurodegenerative disease. Deep and rigorous mechanistic studies the cause of SCA2, like this one, may someday give rise to new approaches to treat broader spectrum of neurodegenerative disorders.

Key Terms

Autophagy: One way that cells get rid of misfolded proteins by breaking them down. Autophagy literally means self-eating and serves as a quality control mechanism. Defects in autophagy have been linked to several neurodegenerative disorders.

Caspase-9 and Caspase-8: Two proteins that can indicate cells are under a lot of stress or are dying. Low levels mean cells are healthy. High levels mean cells have an unhealthy amount of stress.

CAG-repeat diseases: Also called polygltuamine expansion disease, they are a family of diseases caused by an expansion of glutamine amino acids in certain proteins. You can learn more in the Snapshot we did about polygltuamine expansion.

Congo red: A compound has been shown to help dissolve aggregated proteins in other neurodegenerative diseases. It used to be used to dye cotton, but has been replaced with more modern dyes.

Conflict of Interest Statement

The author and editor declare no conflict of interest.

Citation of Article Reviewed

Wardman, J.H., Henriksen, E.E., Marthaler, A.G., Nielsen, J.E. and Nielsen, T.T., 2020. Enhancement of Autophagy and Solubilization of Ataxin-2 Alleviate Apoptosis in Spinocerebellar Ataxia Type 2 Patient Cells. The Cerebellum19(2), pp.165-181. DOI: 10.1007/s12311-019-01092-8

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