1- Understanding how protein dysfunction contributes to neurodegeneration
Neurodegenerative disease, including Alzheimer’s disease, amyotrophic lateral sclerosis and frontotemporal dementia, are age-related complex disorders that are characterized by the death of nerve cells in the brain and spinal cord of people living with these conditions.
Despite the differences in the age of onset and symptoms across all neurodegenerative disease, there are striking similarities at the cellular and molecular level including protein dysregulation. Indeed, harmful changes to the protein structure (e.g. formation of clumps), and function (e.g. loss of the normal protein function or gain of a toxic function) are common hallmarks of neurodegenerative disease.
We focus in particular on post-translational modifications (PTMs) of proteins, which are molecular switches that can regulate the structure and function of proteins, and how they play a role in neurodegenerative disease. Our research is based on the discovery that in neurodegenerative disease, proteins often present abnormal modifications that impair their function in cells, which ultimately can trigger cell death. In particular, using gene editing and recombinant protein-based functional assays, we explore how certain types of cellular stresses (esp. oxidative and nitrosative stresses) can lead to abnormal modifications of proteins and protein dysfunction in neurodegenerative diseases.
Our group aims to uncover what causes these harmful changes to protein structure and function in the brain of people living with neurodegenerative disease and to find ways to prevent these changes from occurring in order to slow down or stop the disease progression.
2- Exploring cell-cell (mis)communication in brain ageing and neurodegenerative disease
We explore the communication between the various cell types of the human brain, as well as between the cells of the brain and of other organs of the body. We focus in particular on one crucial mode of cell-cell communication that is mediated by the secretion from the cells of an array of proteins in the extracellular milieu. Using secretomics, we investigate whether, and how, miscommunication between cells contributes to ageing and to neurodegenerative disease.
Because secreted proteins can ultimately reach the general blood circulation, they represent easily-accessible markers that are potentially characteristic of certain diseases or certain disease stages. Our approach allows us to identify new circulating ‘biomarkers’ that could be used in the future to help diagnose neurodegenerative disease more efficiently and rapidly.
3- Developing novel cellular models for neurodegenerative disease
Most clinical trials aiming at treating neurodegenerative disease have so far failed. One reason for this is the lack of good models that would recapitulate all the key features of neurodegenerative disease and that could be used in the lab to discover new drugs to treat these disorders.
To fill this gap in knowledge, our group is developing new cellular models for neurodegenerative disease. Using stem cell technology, we are currently developing advanced cellular models that combine culture of multiple cell types in 3D hydrogel matrices to try to best mimic – in a dish – how cells behave in the human brain. We also use gene editing to introduce in our cellular model the same genetic mutations found in people living with neurodegenerative disease; this allows us to explore how patient mutations affect the function and survival of the various cell types of the brain.
We will use our new cellular models to shed light on the molecular mechanisms underpinning neurodegenerative disease and to test the efficacy and toxicity of new drugs for these disorders.
4- Finding drugs to treat neurodegenerative diseases
With a global ageing population and the lack of effective disease-modifying therapies, age‐related neurodegenerative disease are an increasing public health concern. The longer-term goal of our group is to translate our findings emerging from our fundamental research on neurodegenerative disease into the development of new treatments that would benefit people living with these disorders.
Based on computational predictions and in vitro drug screening, we aim to uncover new drugs that could restore the normal function of proteins we have previously identified as being dysfunctional in neurodegenerative disease.