Biography
Research theme 1: Understanding the role of protein mislocalization in neurodegenerative diseases
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 2: Regional vulnerability in neurodegenerative disease
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.
Research theme 3: Ascribing medical value to genetic variance in neurodegeneration
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.
Selected publications
- Rousseaux MW*, Tschumperlin T*, Lu HC*, Lackey EP, Bondar V, Wan YW, Tan Q, Adamski CJ, Friedrich J, Twaroski K, Chen W, Tolar J, Henzler C, Sharma A, Bajic A, Lin T, Duvick L, Liu Z, Sillitoe RV, Zoghbi HY, Orr HT. ATXN1-CIC complex is the primary driver of cerebellar pathology in spinocerebellar ataxia type 1 through a gain-of-function mechanism. Neuron. 2018 Mar 21. https://doi.org/10.1016/j.neuron.2018.02.013 * = Authors contributed equally
- Rousseaux MW, de Haro M, Lasagna-Reeves CA, De Maio A, Park J, Jafar-Nejad P, Al-Ramahi I, Sharma A, See L, Lu N, Westbrook TF, Troncoso JC, Botas J, Zoghbi HY, TRIM28 regulates the nuclear accumulation and toxicity of both alpha-Synuclein and tau, eLife. 2016 Oct 25, 10.7554/eLife.19809
- Jung SY*, Choi JM*, Rousseaux MW*, Malovannaya A, Kim JJ, Kutzera J, Wang Y, Huang Y, Zhu W, Maity S, Zoghbi HY, Qin J, An anatomically resolved mouse brain proteome reveals Parkinson disease-relevant pathways, Mol. Cell. Prot. 2017 Apr;16(4):581-593. doi: 10.1074/mcp.M116.061440. Epub 2017 Feb 2.
* = Authors contributed equally - Rousseaux MW, Marcogliese PC, Qu D, Kim RH, Slack RS, Schlossmacher MG, Lagace D, Mak TW, Park DS, Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson's disease, PNAS. 2012 Sep 25;109(39):15918-23.
- Jeong HH, Kim SY, Rousseaux MW, Zoghbi HY, Liu Z, CRISPRcloud: A secure cloud-based pipeline for CRISPR pooled screen deconvolution, Bioinformatics. 2017 May 24. doi: 10.1093/bioinformatics/btx335.
- Lasagna-Reeves CA, de Haro M, Hao S, Park J, Rousseaux MW, Al-Ramahi I, Jafar-Nejad P, Vilanova-Velez L, See L, De Maio A, Nitschke L, Wu Z, Troncoso JC, Westbrook TF, Tang J, Botas J, Zoghbi HY, Nuak1 regulates tau levels and rescues neurodegeneration in a tauopathy mouse model, Neuron, Oct 19;92(2):407-418.