Translation in Action: Protective response to early changes in ALS and FTD
Prof Adrian Isaacs, Group Leader at the UK DRI at UCL, talks us through his lab’s recent work on early changes in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
COL6A1 staining in spinal cord motor neurons
What does translation mean to you?
To me, translation means utilising the breakthroughs we are making in the lab to accelerate the development of new treatments for patients. This can be through developing new therapeutic approaches as well as new biomarkers to facilitate clinical trials.
Why were you interested in researching this area?
A mutation in a gene called C9orf72 is the most common cause of ALS and FTD. This faulty gene leads to the production of abnormal proteins which are a known feature of the diseases, but their impact has not yet been fully determined. In this study, we set out to generate a new mouse model which more accurately recapitulated the pathology of the disease to examine the impact of these proteins in the brain and spinal cord.
What did you set out to learn and what did your research involve?
We created C9orf72 ‘knock-in’ mouse models to mimic features of ALS and FTD. When we looked at the proteins found in the spinal cord of the mice, we discovered an increase in proteins related to the extracellular matrix, which usually provides structural support to cells – with levels of a protein called COL6A1 most raised.
Further work revealed that a protein called TGF-β1 played a key role in controlling this increase in extracellular matrix proteins. When we experimented with this in human neurons grown in the lab, we found that the abnormal proteins generated by faulty C9orf72 triggered the production of TGF-β1 and COL6A1.
To understand the impact of these findings on the disease, we then conducted experiments in fruit flies and human neurons. We discovered that reducing TGF-β1 or COL6A1 caused neurodegeneration to worsen in fruit flies, while increasing these proteins protected human motor neurons from certain types of damage – suggesting that the proteins could be triggering a protective response in cells.
What is the impact of these findings?
The new model provides insight into early changes that occur in the brains of people with ALS and FTD. It could help to identify new therapeutic avenues to treat these diseases. We unexpectedly found that neurons can mount a neuroprotective effort early in the course of FTD and ALS. It is particularly interesting because this response is observed after a range of neuronal insults including hypoxia, ischemia and excitotoxicity. So whether this response can be harnessed early in the disease course for benefit is now an open question. This provides important new information in our fight to understand and ultimately develop treatments for neurodegenerative diseases.
How will Grays Inn Road change the way you work?
I am really excited about bringing the entire UCL neurodegeneration community into one space at Grays Inn Road. This will greatly facilitate collaboration and enhance the multidisciplinary research needed to deliver new treatments for people with neurodegenerative diseases.
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