Research Grant - 2019

Project Summary:

Accumulation of a protein known as TDP-43 is a hallmark of disease in almost all patients with amytrophic lateral sclerosis (ALS), and many individuals with frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, or diffuse Lewy body disease. TDP-43-associated neurodegeneration in general has been linked to inflammation, and interestingly, these inflammatory signals precede symptoms of disease. This suggests that inflammation contributes to disease pathogenesis, rather than simply acting as a marker of disease. We have now identified the primary innate immune pathway in cells that triggers neuroinflammation due to TDP-43. Unexpectedly this is driven by an innate immune pathway which is an immune sensor that recognises damage to mitochondria, the “powerhouse” of the cell.

Mitochondrial damage triggers inflammation in ALS

We have confirmed previous findings that mitochondria are damaged by TDP-43 in ALS, and identified a specific innate immune sensor for this. Additionally, we have shown this genetically in cell lines and a model of TDP-43 driven disease in vivo. There is also a pharmacological inhibitor of this pathway which we found works in vitro. In this project, we hope to treat established disease in the TDP-43 ALS model and confirm our results in primary human cells, which are both important steps towards getting this therapy into the clinic.

Outcomes:

Our aims in this project were to validate small molecule inhibitors of the immune pathway that triggers neuroinflammation in models of ALS, and also to find biomarkers of this pathway. In order to validate the small molecule inhibitors, we performed tests on stem cell samples from both healthy controls and patients with ALS. We also treated established disease in a mouse model of ALS using the inhibitor and it was found to prevent motor neuron loss, together with the reduction of inflammation as observed in vitro.

To identify biomarkers, we performed blood tests and cerebrospinal fluid (CSF) tests. So far we have been unable to detect elevated levels that were observed in spinal cord samples of patients with ALS. However, we used a different type of blood test in the mouse model of ALS, and these were able to detect a biomarker. We will continue investigating this in future research.

Overall, our project specifically addresses the role of the innate immune system in ALS, which has until now been underappreciated. Our work dramatically redefines this landscape and identifies pathways and molecules that can be broadly investigated in the field of ALS to answer long standing questions regarding disease pathogenesis. We do not argue that neuroinflammation underlies all disease pathology in this complex neurodegenerative disease, but the insights that we have generated are nonetheless critical players that are pharmacologically tractable. This resulted in extremely significant contributions to scientific knowledge and informs future practice of ALS treatment.

Outcomes submitted November 2020.

Publications:

Yu CH, Davidson S, Harapas CR, et al. TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS. Cell. 2020;183(3):636-649.e18. doi:10.1016/j.cell.2020.09.020