Research Theme 1: Understanding the Role of Protein Mislocalization in Neurodegenerative Diseases
Research Theme 2: Regional Vulnerability in Neurodegenerative Disease
Correct protein subcellular localization is fundamental for protein/protein interactions, proper functionality, and downstream processing. If impaired, this can lead to protein degradation (quality control mechanism) or disease. In the case of Parkinson’s disease and ALS, the proteins alpha-Synuclein (a-Syn) and TDP-43 aberrantly accumulate, respectively contributing to disease pathology. The Rousseaux lab works to uncover novel pharmacologically tractable targets to treat disease driven by protein mislocalization with a long-term goal of providing better clinical outcomes for patients.
Research Theme 3: Ascribing Medical Value to Genetic Variance in Neurodegeneration
The question of regional vulnerability in neurodegenerative diseases is a critical but complicated one. Specifically, why the accumulation of one protein leads to the degeneration of a certain area of the brain (and corresponding clinical presentations) whereas another leads to a completely different effect remains enigmatic. To dig into this question, the Rousseaux lab makes use of recently developed epitope-tagged knockin mice to uncover regional differences in toxic protein interactors. Using immunoprecipitation coupled to mass-spectrometry to generate their brain-region specific interactomes, we seek to understand how these interactors impact the selective sensitivity of cells to neuronal death.
Molecular genetics has accelerated the process of understanding disease-gene relationships tremendously. With this large influx of data, however, comes difficulties in separating causal vs. bystander genetic variants; particularly when these variants are of unknown significance. It is therefore critical to rapidly but reliably generate cellular models that depict the human condition; wherein a mutation occurs in the native protein and leads to toxicity over time. The Rousseaux Lab emulates these specific genetic effects, and systematically tests cellular read-outs such as levels, localization, aggregation, and binding partners, to understand the driving molecular changes which lead to disease pathology. These can in turn inform tailored therapies and promote drug development and pre-clinical testing