PhD seminar – Mathieu Bourdenx

Friday 6 December at 11:30 – Venue: Centre Broca

Open to everyone!

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Mathieu Bourdenx, PhD
Senior Research Fellow
UCL, London, UK

Mathieu Bourdenx was a PhD student in Erwan Bezard’s team in 2012-2016. 

Title

From organelles to cell-types: understanding proteostasis dysfunction in ageing and neurodegeneration

Abstract

All cells count on surveillance systems that assure the maintenance of their proteome. Protein quality control decreases with age contributing to the vulnerability of specific cell populations to pathogenic proteins, such as tau. In this talk, I will discuss two complementary projects. First, I will focus on subcellular proteomic analyses of samples from Alzheimer’s disease patients. This unique dataset demonstrates that protein localization dominates over changes in abundance, an aspect that has been vastly overlooked. We have identified, organelle-specific, molecular signatures correlating with tau pathogenic activity, providing new avenues for biomarker development. In the second part of my talk, I will change scale and focus on how brain cell-types are affected by the process of ageing. Combining spatial transcriptomics and single-cell genomics, we have identified neuronal populations uniquely vulnerable to ageing-related proteostasis blockage. Comparing these vulnerable populations to their closest-related resilient cousins allowed to identify novel mechanisms of vulnerability, which are now investigated for modulation.

Key publications

• Watamura N, Foiani M, Bez S, Bourdenx M, et al. In vivo hyperphosphorylation of tau is associated with synaptic loss and behavioral abnormalities in the absence of tau seeds. Nature Neuroscience (in press)
• Bourdenx M, et al. Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome. Cell. 2021 May 13;184(10):2696-2714.e25. doi: 10.1016/j.cell.2021.03.048.
• Caballero B*, Bourdenx M*, et al. Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice. Nat Commun. 2021 Apr 14;12(1):2238. doi:10.1038/s41467-021-22501-9.
• Kirchner P, Bourdenx M, Madrigal-Matute J, Tiano S, Diaz A, Bartholdy BA, Will B, Cuervo AM. Proteome-wide analysis of chaperone-mediated autophagy targeting motifs. PLoS Biol. 2019 May 31;17(5):e3000301. doi: 10.1371/journal.pbio.3000301.
• Bourdenx M, et al. Identification of distinct pathological signatures induced by patient-derived α-synuclein structures in nonhuman primates. Sci Adv. 2020 May 13;6(20):eaaz9165. doi:10.1126/sciadv.aaz9165.