Our research intern, Scarlett Parr-Reid, sits down with Dr. Herrera to discuss his research on spastic ataxia type-8 (SPAX8).
Can you share a little about yourself, your background as a researcher and how you got into the field of rare neurological disorders, specifically ataxia.
My background is in cellular and molecular biology. I work in both the fields of cancer and neurodegeneration. But my main interest is in central nervous system disorders at a cellular and molecular level. In my research, I take information from clinical studies that I can then translate into cellular models. Then, I use those models of disease to visualise and analyse the basic disease mechanisms at the cellular level.
I have worked in the areas of Alzheimer’s disease and Parkinson’s disease, as well as Huntington’s disease. I came to the field of ataxias as there are proteins such as in ARSACS and SPAX8 that people do not know much about. To me, these two disorders are very interesting to study.
Can you share the research you have completed so far into SPAX8?
In healthy people, proteins called NKX6-2 interact with DNA and control the production of certain proteins in the central nervous system. We have previously characterised the mutations in the NKX6-2 gene which cause SPAX8 in living cells. No one has done this work before.
We created a series of genetic tools to monitor healthy and pathological forms of the NKX6-2 protein in cells. In healthy cells, the NKX6-2 proteins naturally concentrate in the nucleus of the cell. But mutations which cause the NKX6-2 proteins to shorten lead to the proteins distributing in different parts of the cell. Some of the NKX6-2 proteins start to aggregate, forming crystals in the cell.
So, we wanted to know whether we could prevent this improper distribution of the proteins by adding in the missing parts of the NKX6-2 proteins. Then, we wanted to know not only if we could get the proteins to go back to the nucleus, but also whether it would then do its normal job in activating the process where genes are formed to make proteins, known as transcription.
How are you able to model the transcriptional activity?
We created a genetic tool which involves the production of a fluorescent protein when the NKX6-2 protein is working properly to activate the transcription of genes.
Can you describe your project ‘Restoring NKX6-2 function by protein complementation: a proof-of-concept’, which was recently funded by Ataxia UK
SPAX8 is a very interesting disorder from a biological and technological point of view, as the protein that causes the disorder, NKX6-2, is very small. The small size of NKX6-2 means that it is easy to manage and work with. This contrasts with the protein that causes ARSACS, sacsin, which is a very big protein.
The shortened versions of the NKX6-2 proteins in SPAX8 offer the opportunity to test a method called protein complementation. This method aims to fix the shorter proteins.
If you fragment a protein into two pieces, the fragments will not be functional. But, if you put the fragments back together, the protein becomes functional again. This is known as protein complementation. We have known this since the 50s. There is also evidence that we can do this for diseased proteins.
Because NKX6-2 is very small, I believe it is possible to put the missing NKX6-2 fragment back in the cell. This would be in the form of a peptide drug, which I believe could reconstitute the function of the short fragment that is present in a patient with SPAX8. I plan to do this in the most severe form of the mutation, where the NKX6-2 protein is the shortest.
Because NKX6-2 is a small protein, we do not need to modify the genome, which is controversial. Instead, we can put the peptide back in as a drug. Read an overview of the project here.
What do you hope your research will achieve, and how could it translate to benefits for patients with SPAX8?
This project is a basic science project and is only one part of the puzzle when it comes to understanding potential methods to treat SPAX8. We need to be able to, for example, look at the cellular processes that come before the NKX6-2 protein is even formed, such as at the genetic level.
In healthy cells, when genetic instructions (called RNA) for a protein are wrong, there is a mechanism to degrade them. They can then be removed for the process to start again. This is called RNA degradation. We need to inhibit this degradation system for our protein complementation method to work. Therefore, this research is not yet applicable to patients.
However, if this research is successful, we will provide the proof-of-concept that this method could be applied to other types of spastic ataxias, where the genetic mutation is less severe, and for whatever reason the degradation system that would normally remove incorrect genetic instructions is not working.
This interview is part one of a two-part series featuring the work of Dr. Federico Herrera. Our next interview will feature his project ‘Towards a pharmacological model of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS)’, which was recently funded by Ataxia UK. Read about this project here.
