Investigating the Tau ubiquitination profile in tauopathies by mass spectrometry

Dementia affects around 55 million people worldwide, and this number is expected to rise in the next years, to reach 152,8 million in 2050. The best-known and common pathology associated with dementia is Alzheimer’s disease (AD), responsible for 60-70% of cases. This pathology is classified as a tauopathy. Tauopathies are defined as a group of heterogeneous neurodegenerative diseases, characterized by an accumulation of abnormal Tau protein in neurons and/or glial cells. The sequestration of Tau in aggregates leads to the loss of function of Tau, causing neurodegeneration. The development of Tauopathies is a multi-step process, which is probably driven by changes in the post-translational modifications (PTMs) of Tau protein. Unfortunately, for almost all of these pathologies, no accurate differential diagnostic methods are available. Numerous studies are currently being conducted with the objective of identifying specific biomarkers for tauopathies. In addition to providing a better understanding of the pathophysiology of tauopathies, the study of PTMs seems to be perfect for identifying these missing biomarkers. According to the literature and previous laboratory results, ubiquitination appears as one of the best ways to identify biomarkers allowing the differentiation of tauopathies. Therefore, the main objective of this master’s thesis is to improve the understanding of these diseases, as well as to validate biomarkers previously identified through the study of Tau ubiquitination. A purification method of ubiquitinated proteins was developed and then applied to human brains affected by several tauopathies (AD, Corticobasal Degeneration, and Pick’s Disease). It allows the identification of the ubiquitinated residues of Tau for each pathology by mass spectrometry analysis. After a bioinformatic analysis of the results, the specific residues have been determined, providing new perspectives to diagnose these pathologies.