Silvia Poggini

Microtubules are essential for neuronal functions and are involved in many neurodegenerative disorders. A posttranslational modification (PTM) of neuronal microtubules, polyglutamylation, was shown to control cargo transport, Tau protein binding to microtubules and to induce early-onset neurodegeneration when exceeding physiological levels. To determine the physiological importance of this PTM, we characterised mouse models with reduced polyglutamylation. We demonstrate that these mice develop late-onset atrophy of the olfactory bulb and frontal cortex, progressively reduced dendritic spine density, and deficits in olfaction, memory, and cognitive control. This indicates an important role of polyglutamylation in neuronal function. To test whether the observed defects are linked to neurodegeneration, we combined mice with reduced polyglutamylation with a transgenic model for tauopathy. Strikingly, reduced polyglutamylation accelerated the premature demise of mice transgenic for human Tau carrying the P301S mutation. Our work thus reveals key roles of microtubule polyglutamylation in neuronal function with implications for late-onset neurodegeneration linked to Tau pathology.

Predicting disease trajectories in patients with major depressive disorder (MDD) can allow designing personalized therapeutic strategies. In this study, we aimed to show that measuring patients’ plasticity – that is the susceptibility to modify the mental state – identifies at baseline who will recover, anticipating the time to transition to wellbeing. We conducted a secondary analysis in two randomized clinical trials, STAR*D and CO-MED. Symptom severity was assessed using the Quick Inventory of Depressive Symptomatology while the context was measured at enrollment with the Quality-of-Life Enjoyment and Satisfaction Questionnaire. Patients were retrospectively grouped based on both their time to response or remission and their plasticity levels at baseline assessed through a network-based mathematical approach that operationalizes plasticity as the inverse of the symptom network connectivity strength. The results show that plasticity levels at baseline anticipate time to response and time to remission. Connectivity strength among symptoms is significantly lower – and thus plasticity higher – in patients experiencing a fast recovery. When the interplay between plasticity and context is considered, plasticity levels are predictive of disease trajectories only in subjects experiencing a favorable context, confirming that plasticity magnifies the influence of the context on mood. In conclusion, the assessment of plasticity levels at baseline holds promise for predicting MDD trajectories, potentially informing the design of personalized treatments and interventions. The combination of high plasticity and the experience of a favorable context emerges as critical to achieve recovery.